Background: We studied the role of protein kinase C (PKC), a major regulatory enzyme and an important component of the phosphoinositide signaling system, in depression. Methods: PKC was determined using [3H]phorbol dibutyrate (PDBu) as the radioligand in the membranal and cytosolic fractions of platelets obtained from hospitalized drug-free depressed patients during a baseline period and from drug-free normal control subjects. Results: We observed that the [3H]PDBu binding was significantly higher in the cytosolic fraction obtained from platelets of depressed patients compared to normal control subjects. Conclusions: Our studies indicate increased formation of PKC in platelets of depressed patients. The significance and mechanisms involved in increased PKC in the cytosolic fraction of platelets are unclear, but they suggest that increased PKC may be associated with the pathophysiology of depressive illness.