Potential interactions between nefazodone (200 mg every 12 hours) and propranolol (40 mg every 12 hours) were assessed in 18 healthy male volunteers in an open-label, randomized, three-way crossover study. The nature, frequency, and severity of adverse events during coadministration of nefazodone and propranolol were similar to those observed with either treatment alone. There were no clinically significant effects on vital signs, electrocardiographic results, or laboratory parameters. With coadministration, the maximum peak concentration (Cmax) and area under the concentration-time curve over the dosing interval (AUC tau) of propranolol decreased 29% and 14%, respectively; Cmax and AUC tau of 4-hydroxy-propranolol decreased 15% and 21%, respectively. Despite decreased plasma concentrations of the beta-antagonists, the reduction in exercise-induced tachycardia and post-exercise double product was slightly greater with coadministration than with propranolol alone. Administration of nefazodone alone did not significantly affect either pharmacologic parameter. The pharmacokinetics of nefazodone and its metabolites were largely unaffected during coadministration. Coadministration of propranolol and nefazodone results in modest pharmacokinetic inequivalencies, but no clinically significant alterations of the pharmacodynamics of propranolol.