The effects of cigarette smoking and sex on theophylline clearance, elimination rate constant, and apparent volume of distribution were examined in 28 healthy, young adults given single oral doses of theophylline or aminophylline. Two-way analysis of variance showed no sex effect but a significant effect of smoking habit on theophylline clearance and elimination rate constant. Neither sex nor smoking had an effect on the apparent volume of distribution. The respective mean clearance, elimination rate constant, and volume of distribution were, in nonsmokers, 0.040 +/- 0.008 (SD) liter per hour per kg, 0.084 +/- 0.015 hr-1, 0.47 +/- 0.08 liter per kg; heavy smokers, 0.063 +/- 0.019 liter per hour per kg, 0.129 +/- 0.045 hr-1, 0.50 +/- 0.06 liter per kg; and ex-smokers, 0.051 +/- 0.10 liter per hour per kg, 0.108 +/- 0.025 hr-1, 0.49 +/- 0.08 liter per kg. Cigarette smoking appeared to induce theophylline metabolism as reflected by the mean theophylline half-life in smokers (5.4 hours) versus nonsmokers (8.3 hours). The effect of cigarette smoking on theophylline clearance may be an important consideration in the clinical use of the drug.