Background Radiofrequency ablation (RFCA) of septal accessory pathway (SAPs) locations is associated with a significant rate of first procedure failures and complications. Several single-center studies suggest that cryothermal ablation might be a safer alternative. The purpose of our study was to systematically review the available literature, including the nonpublished experience of our center, and to compare the safety and efficacy of RFCA vs cryoablation of SAPs. Methods We conducted an electronic search in MEDLINE guided by key terms. In addition, manual review of editorials, review articles, textbooks, and guidelines was undertaken. The search was restricted to studies in humans and publication dates between January 1991 and December 2012. We recorded patient numbers, demographics, procedural data, outcome data, and procedural complications. A random effects meta-analysis model was performed using Stata (version 10.1, StataCorp, College Station, TX). Results Of the 927 articles screened, 128 were selected for detailed review and 55 were finally retained for analysis: 35 reported RFCA between 1991 and 2012, 20 articles reported cryoablation between 2002 and 2012. Of them, 24 studies referred totally or partially to pediatric patients. Additionally, we included our single-center experience of 118 consecutive SAPs undergoing cryoablation. Overall, 3775 patients constitute our study population: 3328 in the RFCA cohort and 447 in the cryoablation cohort. Efficacy outcomes consistently favored RFCA compared to cryoablation. Acute procedural success rate of cryoablation was 84% (95% confidence interval [CI] 78%–88%) vs RFCA 90% (95% CI 87%–92%). Recurrence rate of cryoablation was 21% (95% CI 18%–26%) vs RFCA 11% (95% CI 10%–12%). Long-term success rate after multiple ablation procedures of cryoablation was 73% (95% CI 63%–81%) vs RFCA 90% (95% CI 86%–93%). There were no reported cases of persistent AV block with cryoablation compared to 2.8% (95% CI 2.2%–3.5%) with RFCA. Conclusions Studies of RFCA for treatment of SAPs report higher efficacy rates than do studies using cryoablation. However, the excellent safety profile of cryoablation makes it the energy of choice in high-risk SAP ablation, particularly in young individuals.