Seasonality of mood disorders might involve alterations in the rhythmicity of serotonin [5-HT] function. We examined seasonal effects on the neuroendocrine and mood responses to L-tryptophan (L-TRP) in depressed patients and healthy subjects. In this study, 126 drug-free patients with DSM-III-R major depression and 58 healthy subjects received in i.v. infusion of L-TRP. Serum prolactin (PRL) and plasma tryptophan levels were measured. Mood was assessed with visual analogue scales. Cosinor analysis revealed seasonal variation in peak change (delta) PRL and baseline tryptophan levels in the combined depressed and in unipolar, nonmelancholic, and nonpsychotic patients. Peak delta PRL and tryptophan levels were inversely correlated in combined depressed and unipolar patients. Seasonality was more evident in female than in male patients. These data support previous evidence that 5-HT function is abnormal in depression and further suggest a seasonal variability of such abnormalities that is absent in healthy subjects.