S-20098 has potent and specific agonist properties on melatonin receptors both in vitro and in vivo. Behavioral studies on rodents already showed that repeated intraperitoneal administration of S-20098 could dose-dependently alter the functioning of the circadian clock. To determine whether single administration of S-20098 could alter the circadian rhythms of rodents, we first used the phase-response curve (PRC) approach in two different species: Syrian hamsters and mice (C3H/HeJ). Our results show that the shape, circadian times and extent of the PRC to S-20098 look very similar in mice and hamsters. In both species, the phase advance portion of the PRC to S-20098 is limited to a 3 h window preceding the onset of locomotor activity, but the magnitude of phase shifts is larger in mice. We also tested the phase shifting effects of increasing doses of S-20098 during the interval of maximal sensitivity to this compound. Treatment with S-20098 induces dose-dependent phase shifts, with maximal shifts observed after injections of 20 and 25 mg/kg S-20098 i.p., respectively, in mice and hamsters. Those results are in agreement with the limited distribution of melatonin-binding sites within the circadian clock of adult Syrian hamsters, as compared to other rodents.