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Scientist David Banner has the idea to create super soldiers by introducing modified DNA sequences extracted from various animals to strengthen the human cellular response, but General Thaddeus Ross denies him permission to use human subjects. Banner subsequently conducts the experiments on himself. After the birth of his son Bruce, he finds that his son may have inherited the effects and seeks a cure, but is stopped in the process.

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Years later, Bruce is a geneticist working with his ex-girlfriend, Betty Ross, within the Berkeley Biotechnology Institute on nanomed research. The pair hopes to achieve instantaneous cell repair by using low level Gamma radiation exposure to activate the nanomeds once they are introduced into a living organism. During routine maintenance of their appropriated gamma-ray spectrometer, a circuit shorts and triggers the experiment's program sequence.

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Bruce has a nightmare about the event, he realises his father thought he was a monster and tried to kill him while his mother protected him. This leads to a more powerful transformation into the Hulk. While attempting to gain a sample of the monster, Talbot is killed. The Hulk escapes Desert Base and rampages across the desert to San Francisco, battling Army forces sent after him. Betty calms Bruce into his human form. David tries to taunt his son into transforming into the Hulk, but fails. He then decides to "go first" and bites an electrical cable, absorbing all the electricity in San Francisco.

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The electricity hits Bruce, triggering his own transformation. A brutal fight ensues between David and the Hulk, with David absorbing the Hulk's energy. It proves too much for David to handle, but when he himself transforms into a massive creature, he is killed by an Army missile.

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General Ross suspects Bruce of collaborating with David Banner but deduces Bruce has repressed memories. He orders Bruce to be put under house arrest. Through a phone call with his father, Bruce learns that the radiation unleashed something that was already in his DNA, and that David Banner plans to have Betty killed by his dogs, which now have similar powers to the Hulk thanks to David mutating them with gamma radiation. Bruce is then attacked by Major Glenn Talbot, leading to a transformation into the Hulk.

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The Hulk seriously injures Talbot before leaping to save Betty. After being wounded in a lengthy struggle, he kills David's dogs and changes back into Bruce before being captured by the military the next morning. Bruce is kept under observation at a secret desert base, while Talbot intends to weaponize the Hulk's powers. David tries to recreate Bruce's failed experiment, but instead of turning into another Hulk he finds himself able to absorb any material he touches or energy to which he is exposed. He hands himself over to the military after lying to Betty and telling that he had murdered his wife in front of the child Bruce.

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Unable to prevent the machine from firing, Bruce throws himself in front of a colleague to shield the man and is exposed to a massive amount of gamma radiation.Betty visits Bruce in the hospital and remarks that he should be dead, but Bruce feels great. A new janitor at the lab claims that he is Bruce's biological father, of whom Bruce has no recollection. When under extreme stress, Bruce transforms into the Hulk, a huge, humanoid, green-skinned monstrous being who destroys the laboratory.