We investigated platelet adenylyl cyclase activity in 17 subjects with a history of major depression ("depressed subjects") and 20 controls. Forskolin was used to directly activate adenylyl cyclase, while guanine nucleotides (Gpp(NH)p) and fluoride ions were used to measure adenylyl cyclase activity modulated through the G proteins. Forskolin-stimulated adenylyl cyclase was significantly lower in the depressed subjects (p < 0.0005). There was a statistically significant difference in basal adenylyl cyclase activity between male depressed subjects and male controls. The basal adenylyl cyclase activity was also lower in female depressed subjects, but this difference did not reach statistical significance (p < 0.2). The adenylyl cyclase activity measured after stimulation with a guanine nucleotide or cesium fluoride did not differ between control and depressed male or female subjects. Severity of current depression and the current use of antidepressant medication were not related to the lower forskolin-stimulated enzyme activity in the depressed subjects. The difference in forskolin-stimulated adenylyl cyclase activity appears to reflect a qualitative difference in the adenylyl cyclase enzyme activity in persons with a history of major depression.