Rofecoxib and celecoxib were the first cyclooxygenase-2 (COX-2)-specific inhibitors to be marketed as effective anti inflammatory agents. The results of several recent trials and a meta analysis of currently available studies all demonstrate a greater incidence of increased blood pressure, edema, and cardiovascular events in subjects treated with rofecoxib compared with celecoxib. As an approach to the assessment of molecular mechanisms that may contribute to these cardiorenal differences, this study investigated the inhibitory effects of celecoxib on renal carbonic anhydrase enzyme activity in human hypertensive subjects because in vitro enzyme studies demonstrate such an effect. Ten subjects with stable, treated hypertension were randomized to 1 of 3 treatment sequences, which included, in differing order, 200 mg celecoxib twice a day, 250 mg acetazolamide twice a day, or placebo twice a day. Whereas acetazolamide caused a bicarbonate diuresis and a hyperchloremic metabolic acidosis, celecoxib appeared to have no detectable effect on renal carbonic anhydrase or acid-base homeostasis. Thus, in this short-term study of human subjects, therapeutic doses of celecoxib did not appear to have a clinically significant inhibitory action on renal carbonic anhydrase.