The effect of melatonin on age-related thymic involution and peripheral immune dysfunctions was investigated. Exogenous melatonin was administered through the drinking water (15 microg/ml) of 22-month-old female C57BL mice for 60 consecutive days. Our results show that melatonin distinctly reversed the age-related thymic involution as revealed by the notable increase of thymus weight, total number of thymocytes and percentage of thymocytes at G2+S phases. More strikingly, spleen weight, total number of splenocytes and some peripheral immune capacity such as mitogen responsiveness and NK cell activity were also significantly recovered by 60 days of melatonin application in aged mice. Our findings demonstrate that even when the melatonin supplementation begins late in life, the age-related thymic involution and peripheral immune dysfunctions can be restored at least partially in old mice.