The pharmacokinetics of dexamethasone alcohol is described in six male and six female healthy adult volunteers who each received 8 mg of dexamethasone phosphate by bolus intravenous injection. Quantitation of the alcohol was done using a high-performance liquid chromatographic method with improved specificity. Statistical evaluation of the results generated by nonlinear least-squares regression analysis of the plasma concentration-time data shows that the phosphate ester is very rapidly hydrolyzed to the alcohol and a biexponential equation is the simplest polyexponential equation that is consistent with the data. The terminal phase half-life t1/2 beta was significantly greater (P less than 0.05) in males (mean 201.5 min) than in females (mean 142.3 min). They prolonged t1/2 beta in males did not appear to be caused by an impaired capacity to eliminate dexamethasone since the total plasma clearance did not differ between males (mean 24.5 ml/min) and females (mean 242.9 ml/min). There was, however, a high positive correlation between t1/2 beta and Vdss among the 12 adults (r = 0.92, p less than 0.001). There were also significant correlation between Vdss and body weight (r = 0.67, p less than 0.05) and t1/2 beta and body weight (r = 0.80, p less than 0.01). The difference in body weight between the sexes seems to be the main factor contributing to the difference observed in t1/2 beta. An average of only 2.6% of the dose was found unchanged in a 24-hr urine sample, and hence it appears that dexamethasone is primarily eliminated by extrarenal, probably hepatic, mechanisms.