Large doses of doxepin given intravenously to animals cause tachyarrhythmias, and still higher doses lead to a progressive and, finally, lethal bradycardia. The effect of pretreatment with five different beta-adrenoceptor blocking drugs (propranolol, alprenolol, practolol, metoprolol or tolamolol), p physostigmine, or atropine on these toxic actions of doxepin was investigated. Mice were sedated with diazepam. Doxepin was injected i.v. 0.1 mg every 15 sec until death. ECG was recorded at 10 sec after every injection. All five beta-blockers injected i.p. 30 min before doxepin inhibited the doxepin-induced tachyarrhythmias. None of the drugs prevented or postponed the death of mice. Large doses of beta-blockers dose-dependently enhanced the doxepin-induced bradycardia and accelerated death. The cardioselective beta-blocking drugs practolol and metoprolol proved less active in enhancing bradycardia than the third cardio-selective drug, tolamolol, and non-selective propranolol and alprenolol. This difference may have resulted from properties other than beta-blockade since practolol and metoprolol lack the "cardiodepressant" and local anaesthetic properties. Since physostigmine and atropine did not modify the doxepin effects the anticholinergic property may not be important in the severe cardiotoxic effects of doxepin.