Eight healthy men received a single, 1.25 mg dose of digoxin on two occasions, once in an otherwise drug-free control state and again while concurrently receiving alprazolam, 1.5 mg/day. There was no significant difference between control and alprazolam conditions in digoxin volume of distribution (11.0 vs. 11.2 L/kg), elimination t1/2 (46 vs. 41 hours), or total clearance from serum (2.8 vs. 3.6 ml/min/kg). Alprazolam coadministration slightly reduced mean 96-hour urinary excretion of digoxin (37.6% vs. 30.9% of dose; P less than 0.01), but there was no significant difference between treatment conditions in projected total cumulative excretion of digoxin (45.2% vs. 40.9% of dose) or in renal clearance of digoxin (1.23 vs. 1.44 ml/min/kg). Creatinine clearance also did not differ between the control and alprazolam conditions (164 vs. 142 ml/min). Thus therapeutic doses of alprazolam do not significantly alter digoxin clearance in healthy man.