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"Shoot them in the head."

In 2005, WilPharma's head of R&D released the t-virus in a Harvardville Airport Terminal. The building was locked down and the government sent in the marines along with the Special Response Team to clear out the Zombies.

Leon was selected by the president to take charge of the S.R.T. due to his experience. Under his leadership and advice, they learned how to effectively kill the zombies and rescued five survivors including Claire Redfield.

After saving them, Leon was involved in the fight with Curtis Miller, the Marines, and Angela Miller at WilPharma. He was able to save Angela and kill the G-virus-infected Curtis Miller. At the end, he, Claire, and Angela exposed Frederic Downing for escaping Raccoon City with the "t" and G-virus sample, the t-virus incident at the airport, and setting a time bomb in the WilPharma building in order to secretly sell the last of the G-virus data, t-virus along with its vaccine, and the G-virus.

As the incident comes to a close, Leon is called in for yet another mission. He and Claire parted ways, with the two hoping that they will each meet again someday under far more "normal" circumstances.