The story revolves around an amnesiac girl named Ryoko Otonashi who is an Ultimate Analyst, and the sharp-tongued Ultimate Neurologist Yasuke Matsuda, with whom she is infatuated.

She receives regular treatment from the latter for her psychological disorder, which causes her constant loss of short and long-term memories.

However, Ryoko is connected to the despair incident happening soon that Junko Enoshima has planned out.