BACKGROUND The therapeutic goals of atrial fibrillation (AF) patients are to reduce symptoms and prevent severe complications associated with AF. This study compared the efficacy of flecainide versus pilsicainide in reducing the frequency of AF and improving quality of life (QOL) in symptomatic paroxysmal AF patients without structural heart disease. METHODS The Atrial Fibrillation and Quality Of Life (AF-QOL) study was a prospective, multicenter, randomized, open-label crossover study that compared flecainide and pilsicainide as antiarrhythmic drug therapy. Patients were randomized to receive 3 months of treatment with flecainide twice daily or pilsicainide 3 times daily. Each treatment consisted of a dose-finding phase (weeks 1-4) and an efficacy phase (weeks 5-12). Forty-three patients completed the trial. The main outcome was the number of days with documented AF episodes using a patient-operated electrocardiogram. QOL questionnaires (SF-36 and AF-specific QOL scores) were also completed. RESULTS The median (range) AF frequencies (days/8 weeks) were 2 (0-50) in the flecainide treatment group and 1 (0-54) in the pilsicainide treatment group (no significant between-group difference). No significant difference in the first recurrence of AF during the efficacy phase was noted between flecainide and pilsicainide treatments. The frequency and severity scores of AF-related symptoms improved from baseline to the end of the treatment periods. No significant differences in SF-36 or AF-related QOL scores were noted between the treatment groups. CONCLUSIONS This study found no difference in AF frequency or QOL between symptomatic paroxysmal AF patients who received flecainide or pilsicainide.