Although the anti-viral effect of interferon (IFN) varies depending on 24-hour oscillation in the expression of its specific receptor, the mechanism of oscillation remains to be clarified. Here we report that oscillation in the expression of the IFN receptor gene (IFN-/ R1) in mouse liver is caused by the endogenous rhythm of glucocorticoid secretion. Brief exposure of mouse hepatic cells (Hepa 1-6) to corticosterone (CORT) resulted in a significant decrease in mRNA levels of IFN-/ R1. The CORT-induced decrease in IFN-/ R1 mRNA levels was reversed by pretreating the cells with RU486, a glucocorticoid receptor antagonist. The mRNA levels of IFN-/ R1 gene in the liver of adrenalectomized mice were consistently increased throughout the day. However, a single administration of CORT to adrenalectomized mice significantly decreased the mRNA levels of IFN-/ R1 in the liver. Furthermore, the rhythmic phase of IFN-/ R1 expression was modulated following the alteration of rhythmicity in glucocorticoid secretion, which was induced by restricted daily feeding. As a consequence, under manipulation of the feeding schedule, 2'-5' oligoadenylate synthase activities, as an index of anti-viral effect, in plasma and liver at 24 h after IFN- injection also varied depending on the alteration of glucocorticoid secretion rhythm. These results suggest that the endogenous rhythm of glucocorticoid secretion is involved in the circadian regulation of IFN-/ R1 expression in mouse liver. Our findings also support the notion that monitoring the 24-hour variation in IFN receptor function is useful for selecting the most appropriate time of day to administer IFN.