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Deep Six opens in 1966 aboard the refitted liberty ship San Marino on its way from San Francisco to [[Auckland, New Zealand|Auckland,
Deep Six
New Zealand]]. The ship is carrying more than eight million dollars worth of titanium ingots as well as a mysterious passenger who goes by the name of Estelle Wallace. Wallace is actually Arta Casilighio, a former bank teller at the Beverly-Wilshire bank who embezzled more than $120,000 and is making her getaway. Unfortunately, for her and the rest of the crew, a group of Korean seamen who came aboard as last-minute crew replacements have hijacked the ship and its cargo, and conveniently dispose of Wallace and the crew by paralyzing them with poison in their food and dropping them over the side into the depths of the ocean.

The story then flashes forward twenty-three years to the waters off of Augustine Island, Alaska where an extremely deadly poison is moving through the waters, killing everything it comes in contact with. The poison comes to the notice of the Coast Guard cutter Catawaba when it intercepts a derelict crab boat called the Amie Marie. The men sent aboard to investigate discover that the entire crew has died horribly, bleeding from every orifice and their skin had turned black. The boarding party soon begins to exhibit symptoms themselves. The doctor sent aboard orders the captain of the Catawaba to quarantine the crab boat and calls off his symptoms as the poison overtakes him, hoping that this information will help others in their diagnosis.

It is later revealed that the symptoms of the mysterious poison are strikingly similar to those of a deadly biological weapon, called Nerve Agent S, developed by the Rocky Mountain Arsenal outside of Colorado as the ideal weapon for use on troops wearing gas masks and protective clothing. The agent clings to everything and is absorbed through the skin, resulting in almost immediate death. The weapon was eventually discontinued by the Army because it was as deadly to the troops deploying it as it was to the enemy. While en route to be buried in the Nevada desert, an entire boxcar carrying more than 1,000 gallons of Nerve Agent S disappeared.

Dirk Pitt and his friend, Assistant Projects Director Al Giordino are called away from their current project to assist the Environmental Protection Agency's Dr. Julie Mendoza in an effort to find the source of the poison in what is assumed to be a sunken ship. Pitt discovers that the liberty ship Pilottown is embedded into the shore of the island with only her stern exposed to the elements. They board her and discover the containers of the nerve agent but while they are attempting to recover the barrels, the volcano on the island erupts, causing the barrels to shift and inadvertently kill Dr. Mendoza when her biohazard suit is punctured, exposing her to the poison. Pitt vows to get to the bottom of who was responsible for the poison being on the ship and to take his revenge for the death of Dr. Mendoza.

In his attempts to trace the history of the Pilottown, Pitt discovers information on the wreck that leads him to the Alhambra Iron and Boiler Company in Charleston, South Carolina, and from there turns to NUMA computer expert Hiram Yaeger and St. Julien Perlmutter, a family friend and naval historian. They discover that the Pilottown has been part of a complicated web of insurance scams and piracy which saw her name changed several times, from San Marino to Belle Chase, and finally to Pilottown, as her ownership changed through a number of bogus holding companies. Eventually, they tie the ship to Bougainville Maritime Lines, a powerful company owned by the ruthless and mysterious Madame Min Koryo Bougainville.

Bougainville and her grandson, Lee Tong, have entered into an audacious plan with the Soviet Union to engineer the kidnapping of the President of the United States, the Vice President, the Speaker of the House and the President pro tempore of the Senate, the next three men in the line of succession to the presidency, as part of a project code-named Huckleberry Finn. It is revealed that the Soviet economy is in ruins, a famine is spreading amongst the Eastern Bloc nations and the whole Eastern Bloc may be on the verge of collapse. The Soviets have devised a plan that calls for the President to undergo a top-secret Soviet mind control procedure, termed "mind intervention", which uses a combination of an implanted microchip and injected memories from a brainwashed Soviet dissident to allow the Soviet government to control the President's thoughts without his knowledge. The other three men are kept in reserve as the procedure only has about a 60% success rate. In return for carrying out the abduction, the Bougainvilles are to receive one billion dollars in gold, which the Soviets intend to cheat them out of while unaware that the Bougainvilles intend to double-cross them as well.

When the disappearance of the President (and those next in the line of succession) on the Presidential yacht is discovered, Secretary of State Douglas Oates, now the acting president, orders a cover-up of the disappearance while a massive search is under way to find the kidnapped men. Congresswoman Loren Smith, the on again-off again lover of Dirk Pitt, who is on a fact-finding mission aboard the Soviet cruise liner Leonid Andreyev off the coast of the United States inadvertently witnesses Speaker of the House Alan Moran smuggled onto the ship by a KGB agent. When the Soviets discover that Smith knows that Moran is onboard, they kidnap her as well. Pitt discovers that Loren is missing and he and Giordino sneak about the Leonid Andreyev to find her. But after the Bougainvilles detonate a bomb that sinks the ship (part of their double-cross) she is kidnapped by Lee Tong, disguised as a steward, aboard a rescue boat.

Meanwhile, the President, now under control of the Soviets, returns to the White House and announces that while he was gone, he was negotiating a secret disarmament agreement with the Soviet President and has agreed to loan them billions of dollars in hard currency which they may use to purchase food and previously banned American high-technology products. When he further announces his intention to pull the United States out of NATO and bring home all troops and missiles in Europe without the consent of Congress, Congress announces their intention to impeach him from office. The president sends the Army to keep members of Congress from meeting and it appears that the United States now has what the founding fathers feared worst, a dictator in the White House.

Using information from Yaeger and Perlmutter, Pitt determines that the secret lab the Bougainvilles are hiding the remaining captives in is on a barge along the Mississippi River near New Orleans. He and Giordino embark on unauthorized rescue mission with the aid of the local office of the FBI. The agents are ambushed by Bougainville's security guards and it's up to Pitt and Giordino to rescue Loren and the Vice President. In a last-ditch effort to intercept the barge before it can be sunk at sea, Pitt commandeers the riverboat Stonewall Jackson and enlists the help of 40 members of the Sixth Louisiana Regiment of Confederate re-enactors. Armed with smooth bore muskets, as well as two Napoleon cannons that fire improvised charges, they launch an attack against the Bougainville's crew of stone-cold killers armed with automatic weapons, while Pitt attempts to board the barge and rescue Smith and Margolin before it is too late.

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