She became interested in Issei in Volume 11 because of the changes that have taken place for Ddraig, and asked the latter whether he wants to be a Heavenly Dragon or an Oppai Dragon, and talks about the changes in Ddraig's powers and unusual powerups of his host, because his color of armour has changed to crimson instead of his normal red in Cardinal Crimson Promotion state. Ophis plays a big part in Issei's revival in Volume 12 along with the Great Red, who gave Issei part of his flesh, by giving him a portion of her powers. Ophis described Issei as a lecherous faced father.
Although she does not say it, she seems very fond of Issei, as he is her first friend and had offered her a home in his house in Volume 11. She also seems to listen to him, as she refused to fight Crom Cruach because she promised him she wouldn't fight. After Issei recovers from his dragon deitification and learned that Azazel also left to go to the barrier field, Ophis held Issei's hand and comforted him by saying she will stay by his side forever.
Ophis described him as a father with a lecherous face.
Ophis and Rias are shown to have a good relationship. Ophis described her as a crimson haired, big boobed mom, which she enjoyed as she liked being paired up with Issei, who was described as the father.
Ophis and Asia are shown to have a good relationship. Ophis seems to get along with Asia the most out of the other club members, besides Issei, as she blessed Asia with the ability to communicate with dragons. Ophis described her as a sister with normal sized boobs and long gold hair.
Ophis and Akeno are shown to have a good relationship. Ophis described her as another mom with black hair and big boobs, much to her amusement.
Ophis and Koneko are shown to have a good relationship. Ophis described her as a cat.
Ophis and Xenovia are shown to have a good relationship. Ophis described her as an idiot sister with brute strength.
Ophis and Irina are shown to have a good relationship. Ophis described her as a self-proclaiming angel sister.
Ophis and Ravel are shown to have a good relationship. Ophis described her as a bird.
Ophis and Rossweisse are shown to have a good relationship. Ophis described her as a sister looking like she has low happiness and is poor with silver hair.
Ophis is shown to have a good relationship with Rassei as shown in Volume 13 Extra Life where the two are shown to be playing catch with each other. In fact, Ophis mentioned that she will train Rassei.
Ophis and Azazel originally were not on good terms with each other (mainly Azazel), but this improves to the point where no hatred is shown between them.
Ophis and Ddraig seem to be on friendly terms with each other as shown in Volume 11, Ddraig and Ophis were talking with each other about Issei while Issei was in his dying moments.
Ophis hates Great Red because some time after she left the Dimensional Gap, he moved in. Because of this, she decided that 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.
Ophis' spawn. They have shown to have contact with each other, even though they have not seen each other. But Lilith is shown to have interest in meeting Ophis as well as her.
Ophis and Kunou are noted to having a rather good friendship, with Kunou calling her Phis, albeit due to not knowing her true name, and Kunou creating a shrine for Ophis to be treated as the Dragon God.