The House of R’lyeh contains five scenarios that closely follow the events of H.P. Lovecraft stories. They are set in Boston, Providence, the British Isles, continental Europe and the Middle East. None of the scenarios need to be played at set dates or in a set order, but they could be run in the order presented to form a loose campaign using optional links between scenarios to draw investigators from one to the other.

Alternatively, the scenarios may be used to supplement classic Call of Cthulhu campaigns such as The Shadows of Yog-Sothoth and The Fungi from Yuggoth, the latter currently in print as The Day of the Beast, both of which suggest their component scenarios should be interspersed with others.