Previous neuroimaging studies have claimed a left hemisphere specialization for episodic “encoding” and a right hemisphere specialization for episodic “retrieval.” Yet studies of split-brain patients indicate relatively minor memory impairment after disconnection of the two hemispheres. This suggests that both hemispheres are capable of encoding and retrieval. In the present experiment, we examined the possible limits on encoding capacity of each hemisphere by manipulating the “depth” of processing during the encoding of unfamiliar faces and familiar words in the left and right hemispheres of two split-brain patients. Results showed that only the left hemisphere benefited from deeper (more elaborate) encoding of familiar words, and only the right hemisphere benefited from deeper encoding of unfamiliar faces. Our findings are consistent with the view that hemispheric asymmetries in episodic encoding are related to hemisphere-specific processing of particular stimuli. Convergent with recent neuroimaging studies, these results with split-brain patients also suggest that these hemispheric differences are not due to unique specializations in each half brain for encoding memories, but rather, are due to preferential recruitment of the synaptically closer prefrontal cortex to posterior regions processing material-specific information.