Background: Teenage suicide is a major public health concern. Although there is some understanding of the psychosocial factors associated with teenage suicide, little is known about the neurobiologic factors of teenage suicide. Protein kinase C (PKC) is a critical phosphorylating enzyme in the phosphoinositide signaling pathway (which is involved in many physiologic functions in the brain and has been implicated in the pathogenesis of mood disorders) and is also a target for the therapeutic action of mood-stabilizing drugs. Objective: To examine whether the pathogenesis of teenage suicide is associated with changes in PKC. Design: Postmortem brain study. Participants: Seventeen teenage suicide victims and 17 nonpsychiatric control subjects. Main Outcome Measures: Catalytic activity of PKC and protein and messenger RNA levels of various PKC isozymes, such as PKC α, β, and γ, were determined in the prefrontal cortex and hippocampus of both groups. Results: Protein kinase C activity was statistically significantly decreased in membrane and cytosol fractions of the prefrontal cortex and hippocampus of teenage suicide victims compared with control subjects. Statistically significant decreases in protein levels of PKC α, βI, βII, and γ isozymes were also observed in both of these fractions. These decreases were associated with decreases in levels of their respective messenger RNAs. Conclusion: Because many physiologic functions are mediated through phosphorylation by PKC and because PKC is a target for the therapeutic action of psychoactive drugs, our findings indicate that the pathogenesis of teenage suicide may be associated with abnormalities in PKC and that PKC may be a target for therapeutic intervention in patients with suicidal behavior.