In the near future, a Japanese scientist creates a powerful high-tech exoskeleton called "Infinite Stratos" (IS). Possessing technology and combat capabilities far surpassing that of any other arms system, the IS threatens to destabilize the world. Faced with such an overpowered weapon, the world's nations enact the "Alaska Treaty", stating that IS shall never be used for military combat purposes, and that the existing IS technology must be equally distributed to all nations, to prevent any one nation from dominating the others. However, sometime after the IS was introduced, the society undergone a drastic change. As IS can only be operated by women, there is a shift in the power balance between men and women, where women now dominate society over men.

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Ten years after the IS was initially introduced, the world has entered a new age of peace. However, a 15-year-old male Japanese teenager named Ichika Orimura changes everything. During an accidental run-in with a hibernating IS suit, it is revealed that he possesses the innate ability to operate an IS - the only male in the world capable of doing so. Seeing his potential, the Japanese government forcibly enrolls the bewildered young man to attend the prestigious Infinite Stratos Academy, a multicultural academy where IS pilots from all over the world are trained. Thus, he starts a busy high school life surrounded by girls training to become expert IS pilots. While they seem to be enjoying their thrilling school life, the danger of looming threats and enemies are never too far away.