Because of a suggested role of protein kinase C (PKC) in multidrug resistance (MDR) and recent molecular cloning of PKC isozymes, we compared the expression of Ca++-dependent PKCalpha. beta and gamma, and Ca++-independent PKCdelta, epsilon, and zeta isozymes between drug sensitive murine leukemia P388 and its MDR subline P388/ADR, using qualitative and quantitative polymerase chain reaction (PCR) and Western blot techniques. The expression of PKCalpha and PKCbeta mRNA and their proteins was higher in P388/ADR as compared to P388 cells. In contrast, PKCdelta, epsilon, zeta mRNA were decreased in P388/ADR cells as compared to P388 cells. However, at the protein level the expression of PKCdelta, epsilon, and zeta was also increased in P388/ADR cells as compared to P388 cells, suggesting an increased rate of translation of PKCdelta, epsilon, and zeta isozymes in P388/ADR cells. No PKCgamma isozyme was detected by PCR and Western blot analyses. Confocal microscopic examination revealed a distinct pattern of subcellular distribution of PKCbeta isozymes in P388/ADR when compared with P388 cells. This study demonstrates the presence of altered levels of PKC isozymes in P388/ADR cells that may suggest a role of certain PKC isozymes in MDR.