Pentobarbital-anesthetized dogs were pretreated centrally with either metoprolol, a selective beta1 antagonist, or ICI 118,551, a selective beta2 antagonist, prior to a continuous digoxin infusion (2.5 micrograms/kg/min, i.v.). Both agents produced depressant effects on hemodynamic parameters upon central administration. Metoprolol (1, 3 and 5 mg, i.c.v.) significantly increased the lethal dose of digoxin in a non-dose dependent manner, but these protective effects were not evident upon peripheral administration of the drug (5 mg). This protective effect was not due to local anesthetic properties of metoprolol since pretreatment with lidocaine did not alter the toxicity of digoxin. Central beta2 blockade by ICI 118,551 did not alter the doses of digoxin to ventricular arrhythmias or death. These results suggest that beta receptors are not directly involved in the cardiotoxic actions of digoxin. Metoprolol's effects may be attributed to non-specific central depressant activity.