Theophylline pharmacokinetic parameters were compared in healthy males and healthy premenopausal females who were matched for age and smoking status. Twenty-four subjects (including five smokers and seven non-smokers of each sex) received a single dose of aminophylline 6 mg.kg-1, orally or by intravenous infusion. Theophylline half-life was significantly shorter in female non-smokers (FNS) versus male non-smokers (MNS), (FNS = 6.0 h; MNS = 9.3 h), and in female smokers (FS) versus male smokers (MS), (FS = 4.6 h; MS = 6.3 h). Total body clearance was significantly different in FNS versus MNS, (FNS = 43.8 ml.min-1.-1(1.73) m-2; MNS = 37.4 ml.min-1.1.73 m-2), but did not reach statistical significance in FS vs. MS, (FS = 64.2 ml.min-1.1(-1).1.73 m-2; MS = 53.1 ml.min-1.1.73 m-2). Volume of distribution did not differ significantly between groups. Sex differences in theophylline pharmacokinetics exist and may reflect differences in drug metabolism.