The role of intracellular calcium in an APV-insensitive form of long-term potentiation (LTP) has been studied at the hippocampal mossy fiber synapse. Intracellular calcium was buffered by iontophoretic injection of either BAPTA or QUIN-2, into CA3 pyramidal neurons. The slow calcium-dependent after hyperpolarization was used as an indicator of buffering. LTP was elicited in control and in APV-treated cells (6/6 and 4/5 cell, respectively). In contrast, LTP was observed in only 2/9 BAPTA-loaded cells and in 1/4 QUIN-2-loaded cells. The magnitude of LTP for control and APV-treated cells were not significantly different, but both groups showed significantly greater LTP than BAPTA-loaded cells. These results suggest that an increase in postsynaptic calcium is required for the induction of mossy fiber LTP.