Diltiazem and hydrochlorothiazide are widely used to treat cardiovascular disease, often in combination. The purpose of this investigation was to determine whether a drug-drug pharmacokinetic interaction exists between diltiazem and hydrochlorothiazide. In a randomized, crossover, open study, multiple doses of diltiazem (60 mg four times daily for 21 doses) and hydrochlorothiazide (25 mg twice daily for 11 doses) were administered alone and in combination on three separate occasions to 20 healthy male volunteers. Trough and serial blood samples were collected and plasma was assayed for diltiazem, hydrochlorothiazide, and diltiazem metabolites (desacetyldiltiazem and N-desmethyldiltiazem) using HPLC. Total urine was also collected and quantified for hydrochlorothiazide. Coadministered hydrochlorothiazide did not significantly (p > 0.05) alter diltiazem (alone versus combination) steady-state maximum plasma concentration (Css(max); 145 versus 158 ng mL(-1), respectively), time to maximum plasma concentration (t(max); 3.0 versus 2.8 h, respectively); area under the plasma concentration-time curve (AUCss; 688 versus 771 ng x h mL(-1)), oral clearance (Cl(oral); 96.2 versus 88.0 L h(-1)), or elimination half-life (t(1/2); 5.2 versus 5.2 h). Similarly, administration of diltiazem did not significantly (p > 0.05) influence hydrochlorothiazide (alone versus combination) Css(max) (221 versus 288 ng mL(-1)), t(max) (1.8 versus 2.0 h), AUCss (1194 versus 1247 ng x h mL(-1)), Cl(oral) (22.4 versus 21.2 L h(-1)); t(1/2) (9.8 versus 9.6 h), or renal Cl (15.5 versus 15.2 L h(-1)). In conclusion, a clinically significant pharmacokinetic interaction between diltiazem and hydrochlorothiazide does not exist.