To elucidate the importance of nicotine in determining the effects of cigarette smoking, we studied 10 healthy subjects on a research ward who were either smoking their usual brand of cigarettes, smoking high- (HN, 2.5 mg) or low- (LN, 0.4 mg) nicotine research cigarettes, or abstaining. Blood nicotine concentrations were four times as high smoking HN than LN cigarettes. Values while smoking their own brands were intermediate. Cigarette smoking increased mean (24-hr) heart rate (HR), but HR effect did not differ as a function of nicotine exposure. Analysis of the hourly HR pattern showed that smoking increased HR more over the first few hours of the morning, but then followed a circadian pattern similar to that during abstention. HR remained elevated all night even though no cigarettes were smoked. Blood pressures tended to be higher while smoking, but plasma cortisol concentrations throughout the day did not differ while smoking or abstaining. Thus the amount of nicotine consumed when assessed over the whole day has little influence on magnitude of cardiovascular responses to cigarette smoking. Insofar as nicotine contributes to risk, changing nicotine content per se may not alter the risk of sudden adverse cardiac events associated with cigarette smoking.