Post-mortem brain tissue was obtained from a group of patients with well documented clinical histories of affective disorder. 5-Hydroxytryptamine-1 (5-HT1) and 5-HT2 receptor binding to homogenates of frontal cortex (Brodmann area 10) was measured using tritiated 5-HT and tritiated ketanserin respectively. 5-Hydroxyindoleacetic acid (5-HIAA) levels from the same brain samples were measured by reverse-phase high performance liquid chromatography with electrochemical detection. A tendency towards increased 5-HT receptor binding density in patients with major affective disorder was found compared to dysthymic disorder patients and normal controls. No relationship was found between receptor binding densities and metabolite values, nor were the differences in 5-HT binding correlated with time to autopsy, storage time prior to assay, or to clinical variables including DSM-III psychoticism/non-psychoticism and melancholia. Previous antidepressant drug histories were similar in the two patient groups and are unlikely to account for the findings. An increase in postsynaptic 5-HT2 receptor binding in major affective disorder is a possible pathophysiological mechanism which is compatible with the observed down-regulatory effect of antidepressant drugs (although not electroconvulsive therapy) on 5-HT2 sites. The methodological problems inherent in post-mortem studies in affective disorder are discussed.