Atrial fibrillation cannot always be converted to sinus rhythm by transthoracic electrical cardioversion. We examined the effect of ibutilide, a class III antiarrhythmic agent, on the energy requirement for atrial defibrillation and assessed the value of this agent in facilitating cardioversion in patients with atrial fibrillation that is resistant to conventional transthoracic cardioversion. One hundred patients who had had atrial fibrillation for a mean (+/-SD) of 117+/-201 days were randomly assigned to undergo transthoracic cardioversion with or without pretreatment with 1 mg of ibutilide. We designed a step-up protocol in which shocks at 50, 100, 200, 300, and 360 J were used for transthoracic cardioversion. If transthoracic cardioversion was unsuccessful in a patient who had not received ibutilide pretreatment, ibutilide was administered and transthoracic cardioversion attempted again. Conversion to sinus rhythm occurred in 36 of 50 patients who had not received ibutilide (72 percent) and in all 50 patients who had received ibutilide (100 percent, P<0.001). In all 14 patients in whom transthoracic cardioversion alone failed, sinus rhythm was restored when cardioversion was attempted again after the administration of ibutilide. Pretreatment with ibutilide was associated with a reduction in the mean energy required for defibrillation (166+/-80 J, as compared with 228+/-93 J without pretreatment; P<0.001). Sustained polymorphic ventricular tachycardia occurred in 2 of the 64 patients who received ibutilide (3 percent), both of whom had an ejection fraction of 0.20 or less. The rates of freedom from atrial fibrillation after six months of follow-up were similar in the two randomized groups. The efficacy of transthoracic cardioversion for converting atrial fibrillation to sinus rhythm was enhanced by pretreatment with ibutilide. However, use of this drug should be avoided in patients with very low ejection fractions.