The AFFIRM investigators have recommended rate control as the preferred strategy for recurrent atrial fibrillation (AF), but the appropriate strategy for new-onset persistent AF is uncertain. Our study evaluated the AF recurrence rate and the impact of rhythm-control drugs (class 1A, 1C, and 3 antiarrhythmic drugs) on patients with new-onset persistent AF after successful direct-current (DC) cardioversion. Consecutive patients who underwent DC cardioversion of AF from January 1, 1996 to December 31, 1999 were screened for new-onset persistent AF, and 150 patients met the inclusion criteria. After the first DC cardioversion, 50 patients received rhythm-control drugs (rhythm-control group) and the other 100 did not (rate-control group). The 2 groups had similar clinical characteristics except for a lower ejection fraction (44 +/- 14% vs 49 +/- 14%, p <0.01) and a higher proportion of idiopathic dilated cardiomyopathy (20% vs 1%, p = 0.03) in the rhythm-control group versus the rate-control group. During the follow-up period there was a trend toward a lower rate of early AF recurrence at 24 hours after DC cardioversion in the rhythm-control group versus the rate-control group (6% vs 16%, p = 0.11), but there was a high recurrence rate of AF in both groups at 1 month (30% for the rhythm-control group vs 41% for the rate-control group, p = 0.25). At the end of the follow-up period, rhythm-control therapy was abandoned in 78% of the rhythm-control group patients after the failure of 1 to 3 rhythm-control drugs. In the rate-control group, rhythm-control therapy was attempted after AF recurrence in 62 patients but was later abandoned in 48 patients (77%) because of treatment failure. Therefore, the high incidence of treatment failure with rhythm-control therapy suggests that rate control with anticoagulation should be preferred in patients with new-onset persistent AF if AF recurs after DC cardioversion.