Multiple sclerosis (MS) is characterised by the occurrence of patchy CNS demyelinating lesions, leading to various degrees of motor, sensory, affective, and cognitive deficits. MS is associated also with an increased risk of suicide accounting for a substantial rate of death among these patients. Post-mortem studies in suicide victims with various psychiatric disorders demonstrate a decreased concentration of serotonin (5-HT) and its metabolites in the brain. Since 5-HT is a precursor in the synthesis of melatonin and as pineal melatonin content was found to be low in suicide victims, we predicted lower melatonin secretion in suicidal versus non-suicidal MS patients during an acute exacerbation of symptoms. To test this hypothesis, we investigated nocturnal plasma melatonin levels in a cohort of 28 relapsing patients who were admitted consecutively to an inpatient Neurology service, 6 of whom had a history of suicide attempts and were having suicidal ideation at the time of admission. While both cohorts of patients were not distinguishable on any of the demographic data including use of psychotrophic drugs on the day of admission to hospital, the mean melatonin level in the suicidal group was significantly lower than in the control group (19.0 pg/ml +/- 11.9 versus 45.5 pg/ml +/- 27.1; p < .05). These findings support the prediction of the study implicating the pineal gland in the pathogenesis of suicidality in MS and reinforce the concept that a biological rather than a reactive etiology underlies the development of psychiatric symptoms in MS.