Abstract: The ability of daily melatonin and the melatonin receptor antagonist, S22153, to entrain circadian system function was investigated in mice with atypical melatonin rhythm. B6D2F1 mice were first synchronized to a LD 12:12 for ≈2 wk, then exposed to continuous light (LL) until study completion. After 10–18 days of LL exposure, mice received daily subcutaneous (s.c.) melatonin at a dose of 0.1, 1 or 10 mg/kg/day (exp. 1) or daily intraperitoneal (i.p.) S22153 (20 mg/kg/day) with or without melatonin (1 mg/kg/day, exp. 2) at subjective zeitgeber time (ZT) 10 for 19 days. Then all the mice were exposed to LL for another 10 days. Spectral analysis showed that initial LL lengthened the period of both rhythms by ≈1.5 hr as compared with LD 12:12. No entrainment of either rhythm was found in controls. Conversely, daily melatonin-only, S22153-only or their combination set the temperature and activity periods to ≈24 hr and produced a significant increase of the circadian amplitude of both rhythms as compared with controls. However, after treatment withdrawal, the dominant period lengthened to ≈25.5 hr in mice receiving either melatonin or S22153. On the contrary, the period remained close to 24 hr for the 10 days following withdrawal of combined S22153 and melatonin. Such sustained pharmacological resetting of circadian function could display therapeutic potential against external resynchronization resulting from defective photoperiodic entrainment.