In Volume 12, Great Red helped both Ophis and Issei by saving them from the crumbling dimension and restored Issei's body with his powers. Great Red contributed greatly to the resurrection of Issei by giving part of his flesh to Issei, with Ophis providing a portion of her powers in order to stabilize his soul into his new body. He also lends Issei his power during his fight with the Jabberwocky that was created from Leonardo's Annihilation Maker, claiming that the "Beast" (referring to Jabberwocky) was glaring at him.
Ophis hates Great Red because some time after she left the Dimensional Gap, he moved in. Because of this, she has decided she cannot go back home until he has been driven out. Even after he saved the life of herself and Issei, she still wants his neck.