The tolerance to acetylstrophanthidin of eight mongrel dogs was determined before and three to seven weeks after the creation of a side to side aortocaval fistula. The latter resulted in gross cardiac failure and a variable degree of left ventricular hypertrophy. For each tolerance test the dogs were sedated and given acetylstrophanthidin intravenously in a dose of 0·02 mg/kg over 2 min, followed by 0·004 mg/kg/min until toxicity was produced. Toxicity was defined as an ectopic tachycardia continuing for at least 10 consecutive beats or complete atrioventricular block. Acetylstrophanthidin tolerance was markedly reduced after fistula production, the mean toxic dose falling 0·67 ± 0·43 (SD) mg, or 37%, from 0·087 mg/kg to 0·052 mg/kg (P < 0·005). Increased cardiotoxicity to acetylstrophanthidin in these animals may be a direct or indirect consequence of volume overload or may be secondary to induced biochemical or structural myocardial changes.