1. The contribution of peripheral chemoreceptors to the regulation of ventilation during exercise remains incompletely understood. Digoxin has been reported to increase chemoreflex sensitivity in humans. In the present randomized, cross-over, double-blind study, we tested the hypothesis that this increases the ventilatory response to exercise in normal subjects, as assessed by changes in minute ventilation (V(E)) in response to the rate of CO(2) production (VCO(2)). 2. Minute ventilation, end-tidal PCO(2), pulse oximetric O(2) saturation (S(p)O(2)), heart rate and blood pressure (BP) were measured in 11 healthy young male untrained subjects after intravenous infusion of digoxin (0.01 mg/kg) or placebo during normoxia, isocapnic hypoxia and hyperoxic hypercapnoea. All participants underwent a maximum cardiopulmonary exercise test. 3. During normoxia, digoxin increased systolic BP only. During hypoxia, digoxin increased V(E) compared with placebo (P = 0.009) for the same fall in S(p)O(2) (P = NS). Moreover, no significant effects on ventilation and haemodynamic responses were recorded during hypercapnoea. Digoxin increased the V(E) /VCO(2) slope above the anaerobic threshold from 30.4 +/- 2.9 to 32.8 +/- 3.7 (P < 0.05), but did not affect VO(2max). 4. In conclusion, enhanced peripheral chemosensitivity with digoxin increases the ventilatory response to CO(2) production above the anaerobic threshold, but does not affect exercise capacity in healthy humans.