Acetylprocainamide was used to treat 11 patients with previous procainamide-induced lupus syndrome for their cardiac arrhythmias. Three patients from whom procainamide had been withdrawn and whose lupus was in remission did not have a recurrence during a course of acetylprocainamide therapy of a longer average duration than their prior procainamide therapy. Lupus symptoms subsided during treatment in two patients who had symptoms when acetylprocainamide was started. Drug fever developed in one patient, and another had a mild recurrence of lupus symptoms during high-dose acetylprocainamide therapy that regressed with dosage reduction. All patients had small amounts of circulating procainamide from in-vivo deacetylation of acetylprocainamide. These observations strongly support the hypothesis that the aromatic amino group on procainamide is important for induction of the lupus syndrome and that acetylating this amino group blocks the lupus-inducing effect.