Ten healthy adult men participated in a study to evaluate appropriate dosing schedules of cholestyramine to minimize its effect on the absorption of hydrochlorothiazide (HCTZ). A single 8 gm dose of cholestyramine 2 hours before or after HCTZ, 75 mg po, significantly decreased the amount of HCTZ excreted unchanged in the urine over 24 hours (Ae(0-24)) by 65% (P less than 0.01) and 26% (P less than 0.05), respectively, in four subjects. Six subjects randomly received three different schedules: control, single dose of cholestyramine 4 hours after HCTZ, and multiple doses of cholestyramine (-24, -12, and +4 hours) after HCTZ. There were no significant differences in HCTZ kinetics between the control group and the subjects who received a single dose of cholestyramine. Multiple doses of cholestyramine significantly altered HCTZ kinetics, including reductions in Ae(0-24) by 35% (P less than 0.02), AUC(0-infinity) by 32% (P less than 0.01), and Cmax by 31% (P less than 0.01). We conclude that the best dosing schedule for cholestyramine is 4 hours after HCTZ, but there will still be at least a 30% to 35% decrease in the absorption of HCTZ.