Glucocorticoids are metabolized by the CYP3A isoform of cytochrome P450 and by 11-β-hydroxysteroid dehydrogenase type 1 (11β-HSD-1). Experimental data suggest that post-traumatic stress disorder (PTSD) is associated with an increase in hepatic 11β-HSD-1 activity and a concomitant decrease in hepatic CYP3A activity. Trans-resveratrol, a natural polyphenol, has been extensively studied for its antipsychiatric properties. Recently, protective effects of trans-resveratrol were found in relation to PTSD. Treatment of PTSD rats with trans-resveratrol allowed the rats to be divided into two phenotypes. The first phenotype is treatment-sensitive rats (TSR), and the second phenotype is treatment-resistant rats (TRR). In TSR rats, trans-resveratrol ameliorated anxiety-like behavior and reversed plasma corticosterone concen-tration abnormalities. In contrast, in TRR rats, trans-resveratrol aggravated anxiety-like behav-ior and decreased plasma corticosterone concentration. In TSR rats, hepatic 11β-HSD-1 activity was suppressed, with a concomitant increase in CYP3A activity. In TRR rats, the activities of both enzymes were suppressed. Thus, the resistance of PTSD rats to trans-resveratrol treatment is as-sociated with abnormalities in hepatic metabolism of glucocorticoids. The free energy of bind-ing of resveratrol, cortisol, and corticosterone to the human CYP3A protein was determined us-ing the molecular mechanics Poisson-Boltzmann surface area approach, indicating that resvera-trol could affect CYP3A activity.