The effect of an infusion of quinidine, 180 micrograms/kg/Min (base) on the fractional clearance of digoxin (CDIG/Cin) was studied in saline volume-expanded dogs given a constant infusion of digoxin of either 0.0067 micrograms/kg/min (low dose) or 0.120 micrograms/kg/min (high dose). CDIG/CIN decreased 28% from 1.42 +/- 0.36 during control periods to 1.01 +/- 0.03 (P less than .05) with quinidine in dogs given the low dose. In dogs given the high dose of digoxin, CDIG/CIN decreased 22% from 0.76 +/- 0.17 to 0.59 +/- 0.05 (p less than .05) with quinidine. It is concluded that quinidine reduces CDIG/CIN. High doses of digoxin also reduce CDIG/CIN. Inasmuch as quinidine reduces CDIG/CIN to the same extent in the presence of low or high dose digoxin, the effect of quinidine would appear to be mediated through a mechanism different from that of digoxin.