IMPORTANCE: Quality of life is not a standard primary outcome in ablation trials, even though symptoms drive the indication. OBJECTIVE: To assess quality of life with catheter ablation vs antiarrhythmic medication at 12 months in patients with atrial fibrillation. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial at 4 university hospitals in Sweden and 1 in Finland of 155 patients aged 30-70 years with more than 6 months of atrial fibrillation and treatment failure with 1 antiarrhythmic drug or β-blocker, with 4-year follow-up. Study dates were July 2008–September 2017. Major exclusions were ejection fraction <35%, left atrial diameter >60 mm, ventricular pacing dependency, and previous ablation. INTERVENTIONS: Pulmonary vein isolation ablation (n = 79) or previously untested antiarrhythmic drugs (n = 76). MAIN OUTCOMES AND MEASURES: Primary outcome was the General Health subscale score (Medical Outcomes Study 36-Item Short-Form Health Survey) at baseline and 12 months, assessed unblinded (range, 0 worst to 100 best). There were 26 secondary outcomes, including atrial fibrillation burden (% of time) from baseline to 12 months, measured by implantable cardiac monitors. The first 3 months were excluded from rhythm analysis. RESULTS: Among 155 randomized patients (mean age, 56.1 years; 22.6% women), 97% completed the trial. Of 79 patients randomized to receive ablation, 75 underwent ablation, including 2 who crossed over to medication and 14 who underwent repeated ablation procedures. Of 76 patients randomized to receive antiarrhythmic medication, 74 received it, including 8 who crossed over to ablation and 43 for whom the first drug used failed. General Health score increased from 61.8 to 73.9 points in the ablation group vs 62.7 to 65.4 points in the medication group (between-group difference, 8.9 points; 95% CI, 3.1-14.7; P = .003). Of 26 secondary end points, 5 were analyzed; 2 were null and 2 were statistically significant, including decrease in atrial fibrillation burden (from 24.9% to 5.5% in the ablation group vs 23.3% to 11.5% in the medication group; difference –6.8% 95% CI, –12.9% to –0.7%; P = .03). Of the Health Survey subscales, 5 of 7 improved significantly. Most common adverse events were urosepsis (5.1%) in the ablation group and atrial tachycardia (3.9%) in the medication group. CONCLUSIONS AND RELEVANCE: Among patients with symptomatic atrial fibrillation despite use of antiarrhythmic medication, the improvement in quality of life at 12 months was greater for those treated with catheter ablation compared with antiarrhythmic medication. Although the study was limited by absence of blinding, catheter ablation may offer an advantage for quality of life. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2008-001384-11