OBJECTIVES: To compare the efficacy and safety of percutaneous nephrolithotomy (PCNL) and open surgery (OS) for surgical treatment of patients with staghorn stones based on published literatures. MATERIALS AND METHODS: A comprehensive literature search of Pubmed, Embase, CNKI and Cochrane Library was conducted to identify studies comparing outcomes of PCNL and OS for treating patients with staghorn stones up to Jan 2018. RESULTS: There was no significant difference in final-SFR between PCNL and OS (odds ratio[OR]: 1.17; 95% confidence interval [CI]: 0.64, 2.15; p = 0.61), while PCNL provided a significantly lower immediate-SFR compared with OS (OR: 0.29; 95% CI: 0.16, 0.51; P < 0.0001). PCNL provided significantly lower overall complication rate, shorter operative times, hospitalization times, less blood loss and blood transfusion compared with OS (OR: 0.59; 95% CI: 0.41, 0.84; P = 0.004), (weighted mean difference [WMD]: -59.01mins; 95% CI: -81.09, -36.93; p < 0.00001), (WMD: -5.77days; 95% CI: -7.80, -3.74; p < 0.00001), (WMD: -138.29ml; 95% CI: -244.98, -31.6; p = 0.01) and (OR: 0.44; 95% CI: 0.29, 0.68; P = 0.00002), respectively. No significant differences were found in minor complications (Clavien I-II) (OR: 0.72; 95% CI: 0.47, 1.09; p = 0.12) and major complications (Clavien III-V) (OR: 0.5; 95% CI: 0.23, 1.08; P = 0.08). In subgroup analysis, there were no significant differences for overall complications and operative times between mini-PCNL and OS. In sensitivity analysis, there was no significant difference for overall complications between PCNL and OS. CONCLUSION: Our analysis suggested that standard PCNL turns out to be a safe and feasible alternative for patients with staghorn stones compared to OS or mini-PCNL. Because of the inherent limitations of the included studies, further large sample, prospective, multi-centric and randomized control trials should be undertaken to confirm our findings.