Objective: The aim of this study was to evaluate the clinical efficacy and safety outcomes of the treatment with cryoballoon (CB) compared to the treatment with traditional irrigated radiofrequency ablation (RF) for pulmonary vein isolation (PVI) in patients with paroxysmal atrial fibrillation (pAF) and refractory to antiarrhythmic drug therapy (AAD). Design: We conducted a systemic review to find and include more than two randomized controlled trials (RCTs) with at least 20 patients in each of the CB and RF groups. Thereafter, we performed a meta-analysis to compare the treatment with CB and RF in primary outcomes including 1 year free from AF, complications and re-ablation procedures. Additionally, we evaluated procedure time and fluoroscopy duration in both groups. Risk of bias in the individual studies and across studies was assessed using Cochrane methods. Data extraction and synthesis: Two reviewers extracted study data and assessed risk of bias. Primary outcome data were extracted from the time point 1 year after the procedure. The random-effects model was used to calculate the odds ratio with 95% confidence interval. Data sources: Data sources utilized were PubMed and CENTRAL databases up to 16 June 2016. Eligibility criteria for selecting studies: Included studies were RCTs in adults with pAF and refractory to AAD in which CB therapy, including 1st and 2nd generation CB, was compared to the traditional irrigated RF therapy. Clinical outcomes assessed in each RCT were 1 year AF-free survival, complication rates, re-ablations, fluoroscopy time and procedure time. Results: The systematic review identified four randomized controlled trials that reported on comparative clinical outcomes involving 1284 patients. Our meta-analysis demonstrated that CB ablation had a non-significant higher success rate than RF therapy (OR 1.13; 95% CI 0.72–1.77). However, our study showed a relatively higher rate of complications in the CB group (OR 1.20; 95% CI 0.58–2.52). Furthermore, CB treatment was associated with a non-significant, shorter procedure time and marginally prolonged fluoroscopy time in comparison to RF treatment. Conclusion: Our systemic review and meta-analysis revealed further evidence that cryoballoon ablation is an equally effective alternative procedure to the standard radiofrequency treatment with a slightly, non-significant higher freedom from AF 1 year after the ablation and a shorter procedure time.