The electrophysiological properties of the neural pathways between the hippocampus and the entorhinal cortex were studied intraoperatively in 31 patients undergoing anterior temporal lobectomy for medically intractable complex partial seizures. The hippocampus, removed en bloc, was studied histologically and the pathology was correlated with the electrophysiological findings. In 29 of the patients, entorhinal stimulation evoked a characteristic positive-negative potential in the hippocampus. The entorhinal-evoked hippocampal response closely resembled, or was identical to, the spontaneously occurring hippocampal interictal spike discharge. In patients with Ammon's horn sclerosis in whom there was a major loss of neurons in the hippocampal subfields CA1, CA3, and CA4, the evoked responses were of simple morphology and long latency (mean 21.9 msec to the peak of the first potential). In patients with a ganglioglioma in whom the hippocampus was histologically normal, the evoked responses were of greater complexity and shorter latency (mean 11.8 msec). Stimulation at a single entorhinal site evoked similar waveforms at different hippocampal recording sites. Conversely, stimulation at different entorhinal sites evoked similar responses at a single hippocampal recording site. Stimulation of the hippocampus evoked a potential in the entorhinal cortex and, in some instances, in the amygdala, insula, and lateral temporal cortex. These connections may produce a positive feedback loop that favors seizure generation.