Seasonal changes of several serotonin-related measures in plasma and whole blood of healthy individuals were determined every 4 weeks. Plasma serotonin (5-HT) shows very marked changes throughout the year, with maximum values during the summer and lowest values in the fall, whereas its metabolite 5-hydroxyindoleacetic acid (5-HIAA) follows a somewhat contrary pattern. The sum of 5-HT plus 5-HIAA in plasma thus does not change significantly during the year and follows the evolution of total plasma tryptophan (TP). The difference of 5-HIAA minus 5-HT in plasma, which is indicative of the efficacy of degradative processes of 5-HT in the periphery, is strongly dependent on the season and suggests a higher degradation of 5-HT during fall-winter. Unlike plasma TP and whole blood 5-HT, significant correlations among plasma 5-HT, 5-HIAA, and the ambient temperature were found. The possible significance and relationship of these findings to the seasonality of major depression is discussed.