Marijuana (MJ) smoking produces inflammation, edema, and cell injury in the tracheobronchial mucosa of smokers and may be a risk factor for lung cancer. Because oxidative stress may mediate some of these effects, this study was designed to test the hypothesis that cannabinoids in MJ smoke contribute to cellular oxidative stress. Oxidative stress was evaluated in an endothelial cell line (ECV 304) following exposure to smoke produced from MJ cigarettes containing either 0, 1.77, or 3.95% Delta9-tetrahydrocannabinol (Delta9-THC). Brief exposure to smoke from 3.95% MJ cigarettes stimulated the formation of reactive oxygen species (ROS) by 80% over control levels and lowered intracellular glutathione levels by 81%. Smoke-induced ROS generation increased in a dose- and time-dependent manner. In contrast, exposure to smoke from MJ containing 0% Delta9-THC produced no increase in ROS despite a 70% decline in glutathione levels. Smoke from MJ containing 1.77% Delta9-THC stimulated intermediate levels of ROS. A brief, 30-min exposure to MJ smoke, regardless of the Delta9-THC content, also induced necrotic cell death that increased steadily up to 48 h of observation. MJ smoke passed through a Cambridge filter that removed particulate matter was 3.4-fold more active in ROS production compared with unfiltered smoke, suggesting that most of the oxidative effects are produced by the gaseous phase. Alveolar macrophages obtained from habitual MJ smokers displayed low levels of glutathione compared with macrophages from nonsmokers. We conclude that MJ smoke containing Delta9-THC is a potent source of cellular oxidative stress that could contribute significantly to cell injury and dysfunction in the lungs of smokers.