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We explored the effects of resveratrol on oxidative stress in cardiomyocytes subjected to rapid electrical stimulation (RES) and also investigated the underlying mechanisms.Cultured ventricular myocytes of neonatal rat were subjected to RES at 4.0 Hz, with or without resveratrol, an NADPH oxidase inhibitor apocyanin (APO) or a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor autocamtide-2-inhibitory peptide (AIP). Cell counts, to optimize resveratrol concentration, and angiotensin II content were evaluated. Reactive oxygen species (ROS), intracellular Ca2+ in cardiomyocytes, and cardiomyocyte apoptosis were also assessed. Levels of methionine sulfoxide reductase A (MsrA), Nox, oxidative CaMKII (OX-CaMKII), and cleaved caspase-3 in cardiomyocytes were examined.Resveratrol treatment, as compared with APO and AIP, significantly decreased ROS levels, improved Ca2+ amplitudes, and intracellular Ca2+ transient decay rates, and inhibited cardiomyocyte apoptosis. Resveratrol also increased MsrA protein levels. In cardiomyocytes subjected to RES, after pretreatment with resveratrol or APO, protein levels of Nox4, Nox2, OX-CaMKII, and cleaved caspase-3 were decreased. In comparison, with AIP pretreatment, only Nox2, OX-CaMKII, and cleaved caspase-3 were decreased. However, in the presence of dimethyl sulfoxide, a competitive inhibitor of MsrA function, a decrease in cleaved caspase-3 did not occur.Resveratrol decreased ROS, partially through the inhibition of NADPH oxidase activity and upregulation of MsrA expression.