Abstract Background: Membrane protein kinase C (PKC) activity is increased in frontal cortex of subjects with bipolar affective disorder, and lithium was demonstrated to inhibit PKC translocation to membranes. Protein kinase C is anchored to the membrane via the receptor for activated C kinase-1 (RACK1), suggesting that interactions between these proteins may be altered in bipolar disease. Methods: The levels of RACK1 coimmunoprecipitating with PKC isozymes were compared in homogenates of frontal cortex slices from postmortem bipolar subjects and matched control subjects. Results: Receptor for activated C kinase-1 was located exclusively in membranes and, in control brains, the levels of RACK1 that coimmunoprecipitated with most PKC isozymes were increased by stimulation with the PKC activator, phorbol 12-myristate, 13-acetate (PMA). The association of RACK1 with membrane γPKC and ζPKC was increased under basal conditions in bipolar relative to control brains. Stimulation with PMA increased the amount of RACK1 that coimmunoprecipitated with the α, β, γ, δ, and εPKC isozymes, but not ζPKC, in bipolar tissues over that elicited in control tissues. Conclusions: These data suggest that the increased association of RACK1 with PKC isozymes may be responsible for the increases in membrane PKC and in its activation that were previously observed in frontal cortex of bipolar affective disorder brains.