The cardiovascular effects and safety of transdermal nicotine patches were assessed in 50 healthy smokers using repeated 48 hour ambulatory electrocardiographic monitoring as a part of a smoking cessation program. Following baseline measurements, subjects were randomized to active (n = 25) or placebo (n = 25) treatment groups for a period of 2 weeks. Twenty-two patients in each group completed the trial. During the treatment period, subjects also received behavioral supportive therapy. Heart rate and blood pressure were significantly reduced relative to baseline both groups. In the active treatment group, mean values at baseline and after 2 weeks of double-blind treatments were as follows: heart rates, 74.0 and 71.3 beats/min, respectively; systolic blood pressure, 108.9 and 106.9 mmHg; and diastolic blood pressure, 69.7 and 68.2 mmHg, respectively. Values for the placebo group were as follows: heart rate, 73.2 and 69.6 beats/min; systolic blood pressure, 110.6 and 105.3 mmHg; diastolic blood pressure, 71.4 and 70.5 mmHg. The confidence intervals of the mean for the differences between the groups are as follows: heart rate, -4.0 +8.2; systolic blood pressure, -6.7, +10.1; diastolic blood pressure, -7.9, +3.9. There were no changes in the frequency of atrial or ventricular arrhythmia as documented by repeated 48 hour ambulatory ECG recordings from baseline period before stopping smoking compared with the treatment period in the active as well as in the placebo groups. No ischemic events were detected in any of the volunteers during either the baseline or treatment periods. As a measure of smoking abstinence, we assessed the level of carbon monoxide in expired air; in the active group, the mean levels fell from 14.2 to 4.4 ppm after smoking cessation and in the placebo group from 13.2 to 4.2 ppm. The mean urine cotinine level fell from 8.18 mmol/l at baseline to 5.74 mmol/l after 2 weeks of treatment in the active group and from 8.78 to 3.93 mmol/l in the placebo group. The number of cigarettes smoked per week in both treatment groups was significantly reduced: from 175.2 to 8.4 for the active group and from 136 to 8.6 for the placebo group. Eleven out of 22 subjects in each group quit smoking completely. Smoking withdrawal symptoms during the first week of treatment were more severe in the placebo group than in those on active treatment. There were no significant side effects in either the placebo or the active treatment groups. These results indicate that nicotine delivered by transdermal system is free of cardiac adverse effects in healthy volunteers.