Burn trauma causes cardiac dysfunction. However, much of the underlying cellular and molecular mechanisms remain elusive. In the present study, we demonstrate the roles of excessive sarcoplasmic reticulum (SR) Ca 2+ leakage and oxidative stress in burn-associated acute heart failure. In cardiomyocytes from failing rat hearts 12 h after full-thickness cutaneous burn of about 40% of the total body surface area, we found that Ca 2+ transients and contractility were impaired, but the triggering L-type Ca 2+ channel current density was unaltered, giving rise to a significantly reduced gain of excitation–contraction coupling. This deficiency in SR Ca 2+ release was accompanied by a reduction in Ca 2+ content in the SR. Surprisingly, the frequency of spontaneous Ca 2+ sparks was increased by 1.4-fold; Ca 2+ tolerance test (10 mM extracellular Ca 2+ ) further showed 2.0- and 1.5-fold more frequent Ca 2+ waves and Ca 2+ sparks, respectively. Myofilament sensitivity to Ca 2+ , however, seemed to be unaffected. These results suggest hyperactivity of the ryanodine receptor (RyR) Ca 2+ release channel and a leaky SR in burn. Importantly, pretreatment with antioxidant vitamins C and E seemed to prevent burn-induced RyR hypersensitivity and SR leakage and thereby normalize Ca 2+ transients and contractility. Concomitantly, the in vivo cardiac functions were also more tolerant of traumatic burn. Collectively, our findings suggest that SR leakage due to oxidative stress is likely a major candidate mechanism underlying burn-associated acute heart failure. Antioxidant therapy in burn trauma provides cardioprotection, at least in part, by protecting RyR's from oxidative stress-induced hypersensitivity.