The purpose of this study was to investigate the role of the ventromedial prefrontal cortex (vmPFC) in the expression of extinguished heroin seeking as measured by conditioned place preference (CPP) in males Sprague-Dawley rats (n=25). Heroin place conditioning (0.3mg/kg SC x 4 sessions) was followed by a test of preference 24h later, extinction (saline x 4 sessions), heroin reconditioning (saline or 1.0mg/kg x 1 session), and a second test of place preference 24h later. Fifteen minutes prior to this test, rats received intra-vmPFC infusions (bilateral, 0.5 microl/side) of a mixture of GABA(A) (muscimol; 0.03 nmol) and a GABA(B) (baclofen; 0.3 nmol) agonists, or vehicle. As expected on the basis of previous studies, reconditioning with heroin resulted in the re-emergence of a CPP. Importantly, inactivation of the vmPFC produced the same effect in animals that did not receive heroin on the session of reconditioning. These results indicate that the vmPFC modulates expression of extinguished heroin seeking and suggest that prefrontal inhibitory mechanisms are involved in relapse to drug seeking.