The effects of photoperiod and melatonin treatment on reproductive and immune function were assessed in two subspecies of Peromyscus maniculatus from different latitudes of origin. In experiment 1, P. m. bairidii (latitude = 42 degrees 51' N) and P. m. luteus (latitude = 30 degrees 37' N) were housed in either long (LD 16:8) or short days (LD 8:16) for 8 weeks. Short-day P. m. bairdii displayed reproductive regression and elevated splenocyte proliferation in response to the T-cell mitogen concanavalin A, as compared to long-day mice. In contrast, P. m. luteus did not undergo reproductive regression or exhibit any increase in lymphocyte proliferation in short days. In experiment 2, individuals of both P. m. bairdii and P. m. luteus were implanted with empty capsules or capsules that contained melatonin. Individual P. m. bairdii implanted with melatonin underwent reproductive regression. Individuals of this subspecies also displayed elevated lymphocyte proliferation compared to control mice. Conversely, P. m. luteus implanted with melatonin did not undergo reproductive regression and displayed no significant changes in lymphocyte proliferation. These results suggest that reproductive responsiveness to melatonin mediates short-day enhancement of immune function in deer mice. These data also imply that melatonin may not possess universal immunoenhancing properties. Rather, the effectiveness of melatonin to influence immune responses may be constrained by reproductive responsiveness to this indole-amine.