We evaluated the efficacy of K-strophanthidin and digoxin in 20 patients with stable, severe congestive heart failure. In this aim, we studied the left ventricular pump function at rest and following manipulation of the cardiac load (cold pressor test and nitroprusside infusion), the exercise performance (cardiopulmonary exercise test), and the level of circulating norepinephrine. The study was double-blind and cross-over and comprehended 4 periods of 1-week each during which patients received in random order: placebo (oral+intravenous), K-strophanthidin (intravenous + oral placebo), digoxin (oral+intravenous placebo and, in 8 patients, intravenous + oral placebo). The efficacy of the various compounds was tested at the end of each period 1 and 10 hours after drug dosing. Comparable results were obtained by the 2 sets of measurements. Both digoxin and K-strophanthidin showed a positive inotropic effect. This is shown by an upward shift of the ejection fraction/end-systolic stress. In spite of this, only K-strophanthidin significantly increased exercise performance: tolerance time (+153 s), peak oxygen consumption (+1.2 ml/kg/min) and oxygen consumption at anaerobic threshold (+2.3 ml/kg/min). Norepinephrine plasma level at rest was significantly lowered only by K-strophanthidin. Results were comparable when digoxin was given intravenously. We conclude that both glycosides elicit an increase of the inotropic cardiac state but only K-strophanthidin improves exercise performance.