The ventromedial prefrontal cortex (PFC) is implicated in affective and motivated behaviors. Damage to this region, which includes the orbitofrontal cortex as well as ventral sectors of medial PFC, causes profound changes in emotional and social behavior, including impairments in certain aspects of decision making. One reinforcement mechanism that may well contribute to these behaviors is conditioned reinforcement, whereby previously neutral stimuli in the environment, by virtue of their association with primary rewards, take on reinforcing value and come to support instrumental action. Conditioned reinforcers are powerful determinants of behavior and can maintain responding over protracted periods of time in the absence of and potentially in conflict with primary reinforcers. It has already been shown that conditioned reinforcement is dependent on the amygdala, and because the amygdala projects to both the orbitofrontal cortex and the medial PFC, the present study determined whether conditioned reinforcement was also dependent on one or the other of these prefrontal regions. Comparison of the behavioral effects of selective excitotoxic lesions of the PFC in the common marmoset revealed that orbitofrontal but not medial PFC lesions disrupted two distinct measures of conditioned reinforcement: (1) acquisition of a new response and (2) sensitivity to conditioned stimulus omission on a second-order schedule. In contrast, the orbitofrontal lesion did not affect sensitivity to primary reinforcement as measured by responding on a progressive-ratio schedule and a home cage consumption test. Together, these findings demonstrate the critical and specific involvement of the orbitofrontal cortex but not the medial PFC in conditioned reinforcement.