Recent accumulating evidence in animals and humans has shown that memory strengthening occurs, at least partially, during sleep and relies on the covert reactivation of individual memory episodes. However, it remains to be determined whether the hippocampus critically promotes memory consolidation via the reactivation of individual memories during sleep. To investigate the hippocampal-dependent nature of this phenomenon inhumans, we selected two groups of chronic temporal lobe epileptic (TLE) patients with selective unilateral (TLE+UHS) or bilateral (TLE+BHS) hippocampal sclerosis and a group of matched healthy controls, and we requested them to learn the association of sounds cueing the appearance of words. On the basis of other similar behavioral paradigms in healthy populations, sounds that cued only half of the learned memories were presented again during the slow-wave sleep stage (SWS) at night, thus promoting memory reactivation of a select set of encoded episodes. A memory test administered on the subsequent day showed that the strengthening of reactivated memories was observed only in the control subjects and TLE+UHS patients. Importantly, the amount of memory strengthening was predicted by the volume of spared hippocampus. Thus, the greater the structural integrity of the hippocampus, the higher the degree of memory benefit driven by memory reactivation. Finally, sleep-specific neurophysiological responses, such as spindles and slow waves, differed between the sample groups, and the spindle density during SWS predicted the degree of memory benefit observed on day 2. Taken together, these findings demonstrate that the hippocampus plays a crucial role in the consolidation of memories via covert reactivation during sleep.