In two sets of experiments involving 10 smokers, we followed the acute effect of inhaling smoke from cigarettes with five different nicotine yields (0.07 to 1.44 mg) on platelet function in relation to blood levels of carboxyhemoglobin and nicotine. Blood was drawn from fasted subjects who had not smoked for 10 hr before and after smoking one cigarette. Depending on the cigarette, the increase in platelet aggregation to thrombin, adenosine diphosphate, collagen, and epinephrine 10 min after smoking ranged from 0% to approximately 80% for the cigarettes with the higher nicotine yields. Blood nicotine levels increased from 112% to 644%. Clotting activity of platelet-rich plasma (PRP) and platelets rose by 16% with the cigarettes with the highest nicotine contents. Platelet activity correlated with blood nicotine levels but not with carboxyhemoglobin levels. Nicotine diluted in saline solution and added in vitro to PRP from six other subjects 2 min before the aggregation or clotting test at levels after smoking (10 and 20 ng/ml) induced a rise in platelet reactivity of the same order as that after smoking cigarettes. Data suggest that in some cigarettes, nornicotine and substances contained in tar may contribute to the effect of cigarette smoking on platelets.