1. The mismatch response, or mismatch negativity (MMN), is a neurophysiologic response to stimulus change. In humans and other animals, the MMN may underlie the ability to discriminate acoustic differences, a fundamental aspect of auditory perception. 2. This study investigated the role of the thalamus in the generation of a tone-evoked MMN in guinea pigs. Electrodes were placed in the caudomedial (nonprimary) and ventral (primary) subdivisions of the auditory thalamus (medial geniculate nucleus). Surface epidural electrodes were placed at the midline and over the temporal lobe. The MMN was elicited by a deviant stimulus (2,450-Hz tone burst) embedded in a sequence of standard stimuli (2,300-Hz tone bursts). 3. A tone-evoked MMN was present in nonprimary thalamus but was absent in the primary thalamus. Surface-recorded MMNs were measured at the midline but not over the temporal lobe. The correspondence between nonprimary thalamic responses and midline surface potentials, and between primary thalamic responses and temporal surface potentials, is consistent with data reported for the auditory middle latency responses in guinea pigs. 4. The results demonstrate that the nonprimary auditory thalamus contributes to the generation of a tone-evoked MMN in the guinea pig. Furthermore, the data indicate that the guinea pig is a feasible model for investigating central auditory processes underlying acoustic discrimination.