E's Otherwise takes place on a futuristic post apocalyptic earth where 12 huge corporations reign supreme. Since contemporary times, some humans have evolved and can now use special powers, which go beyond abilities normal people are capable of. These folks are referred to as "E's" or nouryoku-sha. In order to control the native E's population, one of the corporations, Ashurum, has created a special task force of E's members. This group, called AESES, assists in the capture and study of nouryoku-sha.
E's Otherwise is the story of Kai Kudo, a shy 15 year old boy with E's powers. Because of his sickly little sister Hikaru, who is also a nouryoku-sha, Kai joins AESES with the promise that she'll receive free medical treatment. Being part of AESES is difficult for Kai, as he must undergo intense training and constant abuse by some of the other E's. In the blink of an eye, a year passes and we find Kai well on his way to becoming a full fledged member. However, his sister is still in a bad state and later a mission goes horribly wrong which leaves Kai abandoned and unconscious by the sea shore.
As luck would have it, he is discovered by pretty young girl, Asuka-chan, who brings him to live with her and her "brother" Yuki. Rather than go back to AESES, Kai decides to stay with the pair and becomes partners with Yuki, who does odd jobs around the town, Gardo, such as bodyguard work, finding people, and cooking! However, things are getting hectic in Gardo, as our duo has to deal with many problems ranging from the ever-present mob, to the power clash between Ashurum and rival corporations for control of the city, to where to find the best seafood ingredients for ramen!