The Guardian of Isis is set in Earth year A.D. 2136—a time approximately four generations after refugees from Earth settled on the planet Isis, the fourth planet of the F-type star Ra in the constellation Indus—in real space, five parsecs from Earth. The settlers are quarantined; beginning soon after their arrival, a message has been beamed into space, warning all ships not to disturb this "original Earth population in Primitive Agricultural Phase." The novel opens in the spring, on "Thanksgiving Day," which commemorates the day of the settlers' arrival in their spaceship, Pegasus Two.