As part of a clinical trial investigating the level of nicotine replacement with different doses of transdermal therapy for smoking cessation, urine excretion rates of nicotine and cotinine were measured in 70 subjects while they were actively smoking (baseline) and for 6 consecutive inpatient days while they were receiving transdermal nicotine therapy. Subjects were stratified according to baseline smoking rate as light (10-15 cigarettes per day), moderate (16-30 cigarettes per day), or heavy (>30 cigarettes per day) smokers and randomly assigned to a daily 24-hour patch delivering a transdermal nicotine dose of 0, 11, 22, or 44 mg. Steady-state excretion rates of nicotine and cotinine were attained in 2 and 3 days, respectively, at all doses and were independent of smoking rate. Percentage replacement of nicotine was calculated by dividing steady-state nicotine or cotinine excretion rates by their respective baseline excretion rates. Significant underreplacement occurred with the 11-mg/day dose, particularly in moderate and heavy smokers (<50%). At a dose of 22 mg/day, nicotine replacement was still <100% in the majority of subjects. Only at a dose of 44 mg/day did mean replacement exceed 100% regardless of baseline smoking rate.