We previously demonstrated that the potent antioxidant, resveratrol, significantly attenuates the adverse cardiac remodeling and dysfunction in pressure overload heart failure induced by transverse aortic constriction (TAC) in C57/BL6 mice. The purpose of this study was to identify the mechanisms that mediate the cardioprotective activities of resveratrol in this setting. Male C57BL6 mice (26-28 g) were subjected to either sham or TAC surgery. One group of TAC mice was given daily resveratrol treatment (oral gavage, 100 mg/kg/body weight for 28 days starting on day 2 after surgery. At the end of the protocol (28 days), the hearts were removed for analysis of markers of oxidative stress, inflammation, and apoptosis. Immunohistological staining for left ventricular (LV) 4-hydroxy-2-nonenal, a marker of lipid peroxidation was significantly elevated in the TAC mice (18.4±3.0 IOD/μm2) compared to sham mice (3.4±1.0). Resveratrol treatment significantly attenuated this increase (14.4±2.0). In contrast, LV content of the antioxidant glutathione was significantly decreased in the TAC mice (5.3±0.2 nM/mg protein) compared to the sham mice (8.5±0.2). Resveratrol treatment significantly increased glutathione (7.6±0.3) to near sham levels. Likewise, LV activity of sodium oxide dismutase 2 was markedly reduced in TAC mice (7.3±0.9 U/mg protein) compared to sham mice (10.7±1.3) and was significantly increased by resveratrol treatment (7.6±0.3). LV macrophage and mast cell infiltration was markedly increased in the TAC mice (14.8±0.1 and 12.6±0.0 %) compared to sham mice (1.7±0.1 and 2.6±0.1). This increase was significantly attenuated by resveratrol administration (10.4±0.1 and 8.0±0.1). Apoptotic cell death, as determined by the TUNEL assay, was also increased in the TAC mice (0.13±0.01 % cells) compared to sham mice (0.01±0.01). This increase was significantly attenuated in the resveratrol treated group (0.06±0.01). A similar pattern was observed when activated LV caspase-3, a second marker of apoptosis, was measured. In conclusion, these data indicate that the cardioprotective effects of resveratrol in pressure overload-induced heart failure are mediated through the inhibition of oxidative stress, inflammation, and apoptotic cell death.