The mediotemporal lobe (MTL), including the hippocampus, is involved in all stages of episodic memory including memory encoding, consolidation, and retrieval. However, the exact timing of the hippocampus' involvement immediately after stimulus encounter remains unclear. In this study, we used high-density 156-channel electroencephalography to study the processing of entirely new stimuli, which had to be encoded, in comparison to highly overlearned stimuli. Sixteen healthy subjects performed a continuous recognition task with meaningful pictures repeated up to four consecutive times. Waveform and topographic cluster analyses of event-related potentials revealed that new items, in comparison to repetitions, were processed significantly differently at 220-300 ms. Source estimation localized activation for processing new stimuli in the right MTL. Our study demonstrates the occurrence of a transient signal from the MTL in response to new information already at 200-300 ms poststimulus onset, which presumably reflects encoding as an initial step toward memory consolidation.