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We investigated whether interictal epileptiform discharges (IED) in the human hippocampus are related to impairment of specific memory processes, and which characteristics of hippocampal IED are most associated with memory dysfunction.Ten patients had depth electrodes implanted into their hippocampi for preoperative seizure localization. EEG was recorded during 2,070 total trials of a short-term memory task, with memory processing categorized into encoding, maintenance, and retrieval. The influence of hippocampal IED on these processes was analyzed and adjusted to account for individual differences between patients.Hippocampal IED occurring in the memory retrieval period decreased the likelihood of a correct response when they were contralateral to the seizure focus (p < 0.05) or bilateral (p < 0.001). Bilateral IED during the memory maintenance period had a similar effect (p < 0.01), particularly with spike-wave complexes of longer duration (p < 0.01). IED during encoding had no effect, and reaction time was also unaffected by IED.Hippocampal IED in humans may disrupt memory maintenance and retrieval, but not encoding. The particular effects of bilateral IED and those contralateral to the seizure focus may relate to neural compensation in the more functional hemisphere. This study provides biological validity to animal models in the study of IED-related transient cognitive impairment. Moreover, it strengthens the argument that IED may contribute to cognitive impairment in epilepsy depending upon when and where they occur.