The association of nocturnal serum melatonin levels was investigated in acute multiple sclerosis (MS) patients with major depression (MD). The sample comprised 13 patients with MD and 12 with no psychiatric disorders admitted to our clinic due to acute MS attacks. Psychiatric evaluation was performed with the Structured Clinical Interview for DSM-IV (SCD-I). The level of depressive symptoms was assessed with the Beck Depression Scale (BDS). Blood samples were taken from the patients to determine melatonin level at 03.30h and 10.00h before steroid treatment started. Melatonin levels were determined using the ELISA test. Nocturnal serum melatonin levels (21.2 ± 17.1 pg/ml) of the patients with MD were significantly lower than those (51.5 ± 18.3 pg/ml) of the patients without MD. A significant negative correlation was found between BDS scores and nocturnal serum melatonin levels. These findings suggest that a melatonin deficiency may be among the factors involved in the occurence of depression in MS patients. © 2007 Elsevier Ireland Ltd. All rights reserved.