Peripheral blood lymphocytes from patients with chronic lymphocytic leukemia (CLL) acquire after several days of exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA) several morphological, immunological and histochemical features of hairy cell leukemia. We have investigated the short term effects of TPA treatment on protein kinase C and its subcellular distribution. Within minutes of addition of TPA to CLL cells 20% of the cytosolic protein kinase C had associated with the particulate fraction. The remaining 80% of protein kinase C activity was down-regulated. The association with the membrane dramatically increased the resistance of the enzyme to inhibition by the non-ionic detergent, Triton X-100. These results suggest that activation of protein kinase C causes multiple biological changes in CLL cells.