The entorhinal cortex projects monosynaptically to the granule cells in the dentate gyrus via the lateral and medial perforant paths. These two subdivisions of the perforant path differ with respect to synaptic properties, and recent studies suggest that they also differ with respect to long-term potentiation (LTP). In the present study, using the in vitro slice preparation of the guinea-pig hippocampus, field excitatory postsynaptic potentials (EPSPs) and LTP in the lateral and medial perforant paths were compared. The two pathways were distinguished on the basis of their different termination in the dendritic layer, their different pharmacology and short-term synaptic facilitation. The field EPSP [obtained in the presence of gamma-aminobutyric acid (GABA) A and B receptor antagonists] consisted of a non-N-methyl-d-aspartate (NMDA) component with different time characteristics in the two pathways, the decay being monoexponential in the lateral perforant path and biexponential in the medial one. In addition, the field EPSP in both pathways contained a small NMDA-mediated component that could also be observed after complete blockade of the non-NMDA one. LTP induction in both lateral and medial perforant paths was facilitated by blockade of GABAA inhibition, showed associative properties, and was blocked by NMDA receptor antagonists. Following the induction event, LTP in both pathways developed to a peak value within 30 - 40 s, and the stability of LTP was correlated with the amount of postsynaptic, but not presynaptic, activity during the induction event. During blockade of GABAA inhibition the opioid receptor antagonist naloxone and the beta-adrenergic antagonist timolol had no effect on the magnitude or stability of LTP. It is concluded that LTP in the lateral and medial perforant paths does not differ with respect to induction mechanisms and early temporal characteristics.