Orbitofrontal cortex (OFC) damage elicits impulsivity and perseveration, and impairments in OFC function may underlie compulsive drug seeking in cocaine users. To test this hypothesis, we assessed the effects of fiber-sparing lesions or functional inactivation of OFC subregions on cocaine seeking in rats. Rats were trained to lever press for intravenous cocaine (0.20 mg/infusion) paired with the presentations of light plus tone stimuli. Responding was then allowed to extinguish. Rats received bilateral NMDA (0.1 M) or sham lesions of the lateral OFC (lOFC) or medial OFC (mOFC) before self-administration training (experiment 1) or muscimol plus baclofen (0.1 and 1.0 mM) or vehicle infusions into the lOFC or mOFC before reinstatement testing (experiment 2). The effects of these manipulations on reinstatement of cocaine seeking (i.e., responding on the previously cocaine-paired lever) were assessed in the presence of the light plus tone stimuli or after a cocaine priming injection (10 mg/kg, i.p.). Post-training lOFC inactivation impaired conditioned cue-induced reinstatement, whereas other manipulations failed to alter this behavior. This suggests that the lOFC plays a critical role in assessing the current motivational significance of cocaine-conditioned stimuli or in using this information to guide cocaine-seeking behavior if stimulus-reward learning takes place before lOFC damage. OFC inactivation failed to alter cocaine-primed reinstatement. However, lOFC lesions augmented cocaine-primed reinstatement in a perseverative manner, whereas mOFC lesions attenuated cocaine-primed reinstatement, suggesting that prolonged cell loss in OFC subregions may modulate the propensity for cocaine seeking in a subregion-specific manner.