The hippocampus and other mesial temporal structures support long-term memory and also are common foci for epilepsy. Recently it was shown that these brain structures may subserve the short-term storage and rehearsal processes called working memory in humans. We determined the accuracy of verbal and visuospatial working memory in the presence and in the absence of mesial temporal spikes in eight patients who had bilateral depth electrodes implanted to evaluate intractable epilepsy. Six of eight patients had declines in working memory performance during mesial temporal spiking, with the greatest disruption in spatial and verbal recall coincident with left hippocampal spikes (p = 0.019). Overall accuracy of working memory for all patients declined an average of 6% on spike trials. The two patients who did not have decreased accuracy during spike trials also had the best overall working memory performance. Mesial temporal spikes were not detected on extracranial recordings and yet may be associated with declines in working memory in some patients with epilepsy.