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Storyline changes from Generations I and III
* The game features entirely new {{player|protagonists}}, {{ga|Chase}} and {{ga|Elaine}}, instead of {{ga|Red}}, and the role of {{ga|Blue}} is replaced with a new friendly [[rival]], {{ga|Trace}}.
* The player and their rival receive their [[Pokédex]] and first {{i|Poké Ball}}s along with their [[starter Pokémon]] and no longer battle until returning to [[Professor Oak]] to deliver [[Parcel|his parcel]]. The player also received some [[Razz Berry|Razz Berries]] from Professor Oak instead of some {{i|Poké Ball}}s.
* The [[Team Rocket trio]] appears early at [[Viridian City]], where they replace the {{ka|old man}} as the obstacle keeping the player from progressing to {{rt|2|Kanto}}. They later can be found in the Pokémon Road in {{rt|17|Kanto}} after the disbandment of Team Rocket.
** Unlike in {{game|Yellow}}, {{MTR|Team Rocket's Meowth}} no longer battles.
* [[Mina]], a {{type|Fairy}} Pokémon Trainer from [[Alola]], is visiting Kanto and can be found in the [[Vermilion City|Vermilion Port]].
* [[Lorelei]] appears early during the {{tc|Team Rocket Grunt}}'s raid near the Pokémon Center on {{rt|10|Kanto}}.
* After killing the {{p|Cubone}}'s mother in [[Lavender Town]], {{TRT}} kidnaps Cubone and takes it back to the [[Team Rocket Hideout]]. They also push away the Team Rocket Grunt blocking access to [[Silph Co.]]. Cubone is later adopted into Trace's team after being rescued.
* Instead of battling the [[Marowak (ghost)|ghost of Cubone's mother]], she is calmed by the presence of her child, Cubone, and then departs.
* [[Archer]], a Team Rocket {{tc|Executive}} who was introduced in [[Generation II]] and given a name in [[Generation IV]], appears during the story.