Background: The optimal first-line approach for patients with symptomatic atrial fibrillation (AF) remains unclear. We compared the efficacy and safety of cryoballoon ablation (CBA) and antiarrhythmic drugs (AADs) in the initial management of symptomatic AF.Hypothesis: CBA is superior to AAD as initial therapy for symptomatic AF.Methods: We searched the EMBASE, PubMed, and Cochrane Library databases for randomized controlled trials (RCTs) that compared CBA with AAD as first-line treatment for AF from the date of database establishment until March 18, 2021. The risk ratio (RR) with a 95% confidence interval (CI) was used as a measure of treatment effect.Results: Three RCTs that enrolled 724 patients in total were included in this metaanalysis. Majority of the patients were relatively young and had paroxysmal AF. CBA was associated with a significant reduction in the recurrence of atrial arrhythmia compared with AAD therapy, with low heterogeneity (RR, 0.59; 95% CI, 0.49-0.71; p < .00001; I 2 = 0%). There was a significant difference in the rate of symptomatic atrial arrhythmia recurrence (RR, 0.44; 95% CI, 0.29-0.65; p < .0001; I 2 = 0%); however, the rate of serious adverse events was similar between the two treatment groups (RR: 1.18; 95% CI: 0.71-1.97, p = .53; I 2 = 0%). Transient phrenic nerve palsy occurred in four patients after the CBA procedure. Conclusion:The current meta-analysis suggests that CBA is more effective than AAD as initial therapy in patients with symptomatic paroxysmal AF. Serious iatrogenic adverse events are uncommon in CBAs.