This study examined the effects of l-arginine on myocardial infarct size, hemodynamics, and vascular reactivity in environmental tobacco smoke (ETS)-exposed and non—ETS-exposed rats. We previously demonstrated that exposure to ETS increased myocardial infarct size in a rat model of ischemia and reperfusion. If reduced reperfusion was caused by endothelial cell damage and increased vascular tone, l-arginine (ARG) would increase nitric oxide and better protect the heart. Sixty Sprague-Dawley rats were randomly divided into four groups: ETS or non-ETS (control) with and without ARG (2.25% ARG in drinking water). The ETS groups were exposed to passive smoking (4 Marlboro cigarettes per 15 minutes, 6 hours a day) for 6 weeks. After 6 weeks, all rats were subjected to 35 minutes of left coronary artery occlusion and 120 minutes of reperfusion, with hemodynamic monitoring. Aortic rings were harvested to evaluate vascular reactivity. Average air nicotine, carbon monoxide, and total particulate concentrations were 1304 ± 215 μg/m³, 78 ± 2.0 ppm, and 31 ± .7 mg/m³ (mean ± SEM) for the ETS-exposed rats. Infarct size (infarct mass/risk area × 100%) increased with ETS exposure but decreased significantly in the ETS-with-ARG group compared with the ETS-without-ARG group (42% ± 6% vs 64% ± 6%, mean ± SEM; p = 0.043). The benefit of ARG was dependent on ETS exposure (ETS × ARG interaction, p = 0.043). There were no significant differences between groups in heart rate, systolic pressure, and rate-pressure product. ARG significantly decreased myocardial infarct size after ischemia and reperfusion in ETS-exposed rats. Neither the adverse effects of ETS on infarct size nor the blockage of this effect by ARG appears to be the result of ETS-induced alterations in hemodynamics.