Objective: The authors' intent was to evaluate the activity of the β- adrenoceptor-linked, cAMP-dependent protein kinase (protein kinase A) in patients with major depression compared with a group of nondepressed volunteer subjects. Method: Skin fibroblast samples were obtained by 2-mm punch biopsy from 12 patients (11 were women) who had major depression diagnosed according to the Structured Clinical Interview for DSM-III-R and from 10 nondepressed volunteers (seven were women). Fibroblasts were cultured in Dulbecco's modified Eagle medium. Baseline and cAMP-stimulated activities of protein kinase A were determined in both particulate and supernatant fractions (900 g). Linkage of the finding to β adrenergic receptor function was evaluated by determination of protein kinase A activity after incubation of the confluent cultures for 30 minutes with 10 μM isoproterenol. Results: There were significant differences between groups in the baseline and cAMP-stimulated phosphorylation in the supernatant fraction. Moreover, the attenuated protein kinase A response was accompanied by a blunted isoproterenol response. Conclusions: Patients with depression exhibit significantly less activity of β-adrenoceptor-linked protein kinase A than do normal subjects. The reductions in protein kinase A activity support the significance of β-receptor-mediated events in depression.