This study was conducted to investigate the frequency of apoptosis in rat cardiomyocytes after intratraperitoneal nicotine injection, in order to examine the roles of inflammatory markers [myeloperoxiclase (MPO) and tumor necrosis factor alpha (TNF-alpha)] in nicotine-induced cardiac damage and to determine the protective effects of three known antioxidant agents (N-acetylcysteine (NAC), erdosteine and vitamin E) on nicotine toxicity in the heart. Female Wistar rats were divided into seven groups, each composed of nine rats: two negative control groups, two positive control groups, one erdosteine-treated group (500 mg kg(-1)), one NAC-treated group (500 mg kg(-1)) and one vitamin E-treated group (500 mg kg(-1)). Nicotine was intraperitoneally injected at a dosage of 0.6 mg kg(-1) for 21 days. Following nicotine injection, the antioxidants were administered orally; treatment was continued until the rats were killed. Heart tissue samples were stained with hematoxylin-eosin for histopathological assessments. Apoptosis level in cardiomyocytes was determined by using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling) method. Staining of cytoplasmic TNF-alpha in cardiomyocytes and heart MPO activity were evaluated by immunohistochemistry. The treatments with erdosteine, NAC and vitamin E significantly reduced the rate of nicotine-induced cardiomyocyte apoptosis. The effect of vitamin E on apoptosis regulation was weaker than the effects of erdosteine and NAC. Erdosteine, NAC and vitamin E significantly reduced the increases in the local production of TNF-alpha and heart MPO activity. This findings suggest that the effects of erdosteine and NAC on apoptosis regulation are stronger than that of vitamin E. Copyright (c) 2007 John Wiley & Sons, Ltd.