Objective: To investigate the association of nocturnal serum melatonin levels in acute multiple sclerosis patients with major depression MD. Methods: 13 patients with MD and 12 with no psychiatric disorders admitted to our clinics due to acute MS attacks were included in the study. Psychiatric evaluation was performed by means of The Structured Clinical Interview for DSM-IV. Level of depressive symptoms was measured via Beck Depression Scale (BDS). Blood samples were taken from the patients to determine melatonin level at 03.30 a.m. and 10 a.m. before steroid treatment started. Melatonin levels were determined using ELISA test. Results: Nocturnal serum melatonin levels of the patients with MD (21.2 ±17.1 pg/ml) were significantly lower than those of the patients without MD (51.5 ±18.3 pg/ml). A significant negative correlation was determined between BDS and nocturnal serum melatonin levels. Conclusion: There is a decrease in nocturnal melatonin secretion rather than phase shift in the multiple sclerosis patients with major depression. This suggests that melatonin deficiency may be among the causes in terms of ethiopathogenesis of depression encountered in multiple sclerosis. We think melatonin replacement could be effective to ameliorate depressive symptoms of MS.