This study investigated the frequency of apoptosis in rat pulmonary artery endothelial cells after intraperitoneal nicotine injection, examining the roles of the inflammatory markers myeloperoxidase [MPO] tumour necrosis factor alpha (TNF-alpha), and vascular endothelial growth factor (VEGF) in nicotine-induced vascular damage and the protective effects of two known antioxidant agents, N-acetylcysteine (NAC) and vitamin E. Female Wistar rats were divided into four groups, each composed of nine rats: negative control group, positive control group, NAC-treated group (500 mg/kg), and vitamin E-treated group (500 mg/kg). Nicotine was intraperitoneally injected at a dosage of 0.6 mg/kg for 21 days. Following nicotine injection, the antioxidants were administered orally; treatment was continued until the rats were killed. Lung tissue samples were stained with hematoxylin-eosin (H&E) for histopathological assessments. Apoptosis level in endothelial cells was determined by using TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick endlabelling) method. Staining of cytoplasmic TNF-alpha and VEGF in endothelial cells, and perivascular MPO activity were evaluated by immunohistochemistry. The treatments with NAC and vitamin E significantly reduced the rate of nicotine-induced endothelial cell apoptosis. NAC and vitamin E significantly reduced the increases in the local production of TNF-a and VEGF, and perivascular MPO activity. This findings suggest that NAC can be as effective as vitamin E in protecting against nicotine-induced endothelial cell apoptosis.