Receptors preferentially activated by the excitatory amino acid N-methyl-D-aspartate (NMDA) do not mediate synaptic transmission in the hippocampus but are involved in initiating long-term potentiation (LTP) in hippocampal region CA1. We have examined the role of NMDA receptors in LTP of the commissural/associational and mossy fiber pathways to region CA3 pyramidal neurons. In the commissural/associational pathway, NMDA receptor blockers did not reduce synaptic responses but reversibly blocked the induction of LTP. In contrast, NMDA receptor blockers had no effect on mossy fiber LTP. These results suggest that induction of commissural/associational LTP differs from mossy fiber LTP, although the mechanisms underlying expression of LTP along these pathways could be similar. Kynurenate and L-2-amino-4-phosphonobutyrate, which potently reduce mossy fiber responses, also did not block induction of mossy fiber LTP.