Serotonin (5-HT) has been implicated in the pathophysiology of depression. It is not known whether depression in post-myocardial infarction (MI) patients is also serotonin-mediated. In somatically healthy depressed persons, increased brain 5-HT(2A) receptor binding has been reported in some studies. In animal studies, decreased serotonin activity was found after induction of MI. In the present study, it was hypothesized that depressed post-MI patients would exhibit increased brain 5-HT(2A) receptor binding compared with non-depressed post-MI patients. Single photon emission computed tomography (SPECT) with the radioligand 123I-5-I-R91150, a 5-HT(2A) receptor antagonist, was used to study 5-HT(2A) receptor binding. SPECT scans were performed in nine depressed post-MI patients, 10 non-depressed post-MI patients and 10 healthy control subjects. Results were analysed using statistical parametric mapping. Depressed post-MI patients showed increased 5-HT(2A) receptor binding compared with non-depressed post-MI patients, and MI patients showed decreased 5-HT(2A) receptor binding compared with control persons. Both post-MI depression and MI seem to be associated with changes in 5-HT(2A) receptor binding.