The effects of dose and sex on the pharmacokinetics of piroxicam were studied in the rat. Piroxicam was administered intravenously at doses of 050 and 5.0 mg kg-' to male and female rats. Plasma drug concentrations were determined by a highly sensitive highperformance liquid chromatographic technique. Non-compartmental pharmacokinetic parameters were calculated by area/ moment analysis. A prolonged terminal half-life averaging 13.3 h in male rats and 404 h in female rats was observed. Dose had no effect on the disposition of piroxicam. The sex of the rat, however, had a marked effect on piroxicam pharmacokinetics, with mean total clearance differing three-fold from 0.0184 1 h-' kg-' in male rats to 0-00622 1 h-' kg-' in female rats. The free fraction of piroxicam in serum was greater in male rats than in female rats owing to a higher association constant for piroxicam binding to female rat serum proteins. Free iroxicam clearance differed and female rats, respectively. Thus, protein binding partially explained the sex-dependent disposition of piroxicam. However, sex-dependent metabolism of the drug also appears to be a major determinant of sex-related differences in piroxicam pharmacokinetics. Steady-state volume of distribution was unaffected by sex. Half-life and mean residence time were three-fold greater in female rats owing to the three-fold lower clearance value compared to male rats.