Orbitofrontal cortex (OFC) damage produces impaired decision-making, impulsivity and perseveration and potentially contributes to compulsive drug seeking in cocaine users. To further explore this phenomenon, we assessed the role of the lateral OFC (lOFC) in drug context-induced cocaine-seeking behavior in the reinstatement model of drug relapse. Rats were trained to lever press for intravenous cocaine infusions in a distinct environmental context (cocaine-paired context) followed by extinction training in a different context (extinction-paired context). Reinstatement of cocaine seeking (non-reinforced lever presses) was assessed in the cocaine context in the absence of response-contingent stimuli. In Experiment 1, we evaluated whether acute inhibition of lOFC output alters context-induced cocaine-seeking behavior by infusing the GABA(B + A) agonists (baclofen + muscimol) or vehicle into the lOFC immediately before exposure to the cocaine-paired context. In Experiments 2 and 3, we assessed how prolonged loss of lOFC output affects drug context-induced cocaine seeking by administering bilateral N-methyl-d-aspartic acid or sham lesions of the lOFC either before or after self-administration and extinction training. Remarkably, IOFC functional inactivation attenuated, post-training lesions failed to alter and pre-training lesions potentiated drug context-induced cocaine seeking without altering responding in the extinction context. These results suggest that neural activity in the lOFC promotes context-induced cocaine-seeking behavior. However, prolonged loss of lOFC output enhances the motivational salience of cocaine-paired contextual stimuli probably by eliciting compensatory neuroadaptations, with the effects of post-training lOFC lesions reflecting an intermediate state of compensatory neuroplasticity. Overall, these findings support the idea that OFC dysfunction may promote cue reactivity and enhance relapse propensity in cocaine users.