Momoko, Miyako, and Kaoru were ordinary girls who lived in Tokyo City... until the white ray hit them and transformed them into the lovely science legend PowerPuff Girls Z!! Three girls suddenly became the superheroines of the city and fought against evil monsters around the town.

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The story starts right after the deadly battle against "Him". The people in Tokyo City enjoy peaceful days. However, Professor Utonium, Ken, and  Peach sense that somebody is preparing an evil scheme to attack Tokyo City.

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Around the same time, Momoko, Miyako, and Kaoru get excited to move on to the sophomore year.  On the first day of a new semester, they meet two girls transferred to Tokyo Middle School, Haine and Luna. Haine is a shy and quiet girl; on the contrary, Luna is an energetic girl who loves dancing. They try to befriend Girls, but they get interrupted by a bunch of classmates.

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After school, the Girls go to Professor Utonium's house and find out that he is trying to do the laboratory experiment――to create the white ray that turns them into PPGZ. The experiment succeeded, but the white ray split into two beams and hit ...Haine and Luna!?​