Abstract: We report on a 10-year longitudinal study on 24-h serum melatonin secretion (AUC) in healthy human subjects. Fifty women and 53 men (aged 42-83 yr) participated in the study initially. Of these, 18 women and 15 men were followed for 6 consecutive years. Results: (a) Cross-sectional analysis (n = 103): A significant (R=−.49, P= .0001) decline in AUC melatonin with age was found in women, but not in men. (b) Longitudinal analysis (n = 33): Repeated-measure ANOVAs for women (n= 18): Time: linear F1,17= 5.14, P= .037. The AUC increased by about 40% over the six-year period. In men, there were no significant changes. Conclusion: In agreement with most cross-sectional studies, an inverse relationship was found between melatonin secretion and age. However, the longitudinal study showed an increase in melatonin secretion, indicating the presence of putative compensatory mechanisms during healthy aging. Changes in melatonin secretion were gender specific, occurring in women only.