Proteolytic activation of protein kinase C (PKC)-delta has been associated with cell death induced by the DNA damaging agent cisplatin. In the present study, we have examined if PKCdelta is affected when cells acquire resistance to cisplatin. The level of PKCdelta was elevated in cisplatin-resistant HeLa (HeLa/CP) cells compared to parental HeLa cells. Prolonged cellular exposure to the PKC activator phorbol-12,13-dibutyrate (PDBu), caused downregulation of PKCdelta in HeLa cells but not in HeLa/CP cells. Treatment of HeLa cells with PDBu resulted in the translocation of PKCdelta from the cytosol to the membrane but it failed to induce PKCdelta translocation in HeLa/CP cells. PDBu, however, induced translocation and downregulation of PKCalpha in both HeLa and HeLa/CP cells. The ability of PDBu to enhance cisplatin-induced cell death was attenuated in cisplatin-resistant HeLa cells. Thus, a deregulation in PKCdelta was associated with reduced cellular sensitivity to cisplatin.