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Sysyphyx is first seen when Connor brings a woman to Mr. Arkham's house and gets her to open a strange chest. Sysyphyx appears from the chest as a many-eyed, spiny worm/snake and attacks the woman, decapitating her. Sysyphyx then attaches herself to the woman's body, uses her shape-changing abilities to mimic the woman's head, and is able to take control of the body.
In this form, Sysyphyx finds a young boy in a comic store and gives him a small, ornate box, which the boy opens at home, eventually transforming him into Gnruk. Sysyphyx takes the place of the boy's mother just before Gnruk emerges, so that he believes it is her and they leave together.
In order to control a mentally-unstable Cy, Sysyphyx changes her face to that of Cy's late girlfriend, Jordan, and they travel to R'lyeh.
At R'lyeh, Raymond tries to stop Sysyphyx, so she changes to his wife to try and manipulate him. Unfortunately for her, Harlot had earlier removed any memories of his wife from his mind, so he had no idea who she was mimicking and simply kicks her off a high ledge into the ocean below...