Introduction: This study examined the effects of antioxidant vitamins on several aspects of sepsis-related myocardial signaling cascades. Methods: Sprague Dawley rats were divided into four groups: Group 1, vehicle treated shams; Group 2, sham rats given antioxidant vitamins (Vitamin C, 24 mg/kg; Vitamin E, 20 U/kg; Vitamin A, 417 U/kg; and Zinc, 3.7 ngkg) by oral gavage in 0.5 ml water twice daily for 3 days and no septic challenge (vitamin treated shams); Group 3, intratracheal delivery of S. pneumoniae, 4x10⁶ CFU in a volume of 0.3 ml phosphate buffer solution; Group 4, S. pneumonia challenge as described for Group 3 plus antioxidant vitamins (as described for Group 2). Hearts collected 24 hrs after septic challenge were used to examine several aspects of cell signaling and ventricular function. Results: Compared with shams, sepsis in the absence of antioxidant therapy promoted NF-B activation, increased mitochondrial cytochrome C release, increased myocyte cytokine secretion, increased caspase activation, and impaired left ventricular function. Antioxidant vitamin therapy plus septic challenge prevented NF-B activation, reduced mitochondrial cytochrome C release, decreased caspase activity, abrogated cardiomyocyte secretion of inflammatory cytokines, and improved myocardial contractile function. Conclusions: Antioxidant vitamin therapy abrogated myocardial inflammatory cytokine signaling and attenuated sepsis-related contractile dysfunction, suggesting that antioxidant vitamins therapy may be a potential approach to treat injury and disease states characterized by myocardial dysfunction.