The capacity of diphenidol to influence ouabain-induced cardiotoxicity was studied in anaesthetized cats with and without spinal cord transection. 2 Diphenidol pretreatment increased the lethal dose of ouabain in both intact cats and cats in which the spinal cords had been transected. Diphenidol pretreatment increased the myocardial content of ouabain associated with death in the intact animals, but failed to influence the lethal ventricular concentration in cats with transected spinal cords. 3 The failure of diphenidol to influence tissue thresholds for toxicity in the spinal cat and the equivalence of tissue ouabain requirements for death in spinal cats and diphenidol-treated intact animals, suggest a neural mechanism for the protective effect in intact animals. 4 Ouabain administration prolonged atrio-ventricular conduction time in all animals and diphenidol attenuated this effect. Thus, the influence of both drugs on antrioventricular conduction may not be entirely mediated by central neurones.