In previous studies we demonstrated that the membrane-associated protein kinase C (PKC) activities in the right and left hippocampus (HIPP) of rats kindled from the left HIPP increased significantly 4 weeks and 4 months after the last seizure compared with those in matched control rats. In this study, we investigated the long-lasting effect of HIPP-kindling on the membrane-associated activities of PKC subspecies in the bilateral HIPP 1 and 4 weeks after the last generalized kindled seizure had occurred. The membrane-associated activities of PKC subspecies were found to be subject to differential regulation. The activity of the alpha-subspecies was unchanged, whereas the respective activities of the beta- and gamma-subspecies in the kindled group increased significantly, compared with the controls, one (21%, P < 0.0001 for the beta-subspecies, and 23%, P < 0.001 for the gamma-subspecies) and 4 weeks (19%, P < 0.02 for the beta-subspecies, and 19%, P < 0.05 for the gamma-subspecies) after the last seizure. There were no significant differences in cytosolic PKC activity between the control and kindled groups for any subspecies examined at either time after the last seizure. These results suggest that activation of the PKC beta- and gamma-subspecies may play an important role in the enduring seizure susceptibility associated with kindling.