Which Pokémon film was the first to feature Mewtwo as its main antagonist?

Pokémon: The First Movie was the first Pokémon film to feature Mewtwo as its main antagonist.

Released in Japan in 1998 and internationally beginning in 1999, the film is officially titled Mewtwo Strikes Back in Japan and Pokémon: The First Movie in many English-speaking markets. Its story follows Mewtwo, a genetically engineered Pokémon created from research on Mew, as it questions its identity and turns against the humans who made it.

The film also features Mew, making the conflict a contrast between a naturally occurring ancestor and an artificial clone. Ash, Pikachu, and their friends are invited to a mysterious island, where Mewtwo’s plan leads to battles between cloned Pokémon and their originals.

The movie is often confused with Pokémon: Mewtwo Strikes Back—Evolution, a 2019 computer-animated remake. The remake revisits the same broad story, but Pokémon: The First Movie is the original theatrical film and the first to place Mewtwo at the center of a feature-length Pokémon narrative.