Abstract: Objective To compare the efficacy and safety of staged retrograde flexible ureteroscopic lithotripsy (FURS) and miniaturized percutaneous nephrolithotomy (m-PCNL) for treatment of renal stones of 2-4 cm in diameter. Methods This randomized controlled trial was conducted in 70 patients with renal stones of 2-4 cm in diameter admitted in our hospital between January 2013 and December 2015. The patients were randomized to receive staged FURS (35 cases) or m-PCNL (35 cases), and the total treatment time, total hospital stay after procedure, total medical cost, treatment success, decrease in hemoglobin level and complications were compared between the two groups. Results The treatment success rate was 100% in both groups, but the complete stone-free rate was significantly lowered in FURS group than m-PCNL group (65.71% vs 94.29%, P<0.01). The average decrease in hemoglobin level was 3.37±1.56 g/L in FURS group and 11.93±2.24 g/L in m-PCNL group (P< 0.01). The overall complication rates in the two groups were 6.25% and 9.37%, respectively (P>0.05). Minor complications (grade I by Clavien-Dindo classification) occurred in one case in FURS group (fever) and two cases in m-PCNL group (self-limiting hematuria); major complications (grade II) occurred in one case in FURS group (steinstrase) and one case in m-PCNL group (blood transfusion). In staged FURS and m-PCNL groups, the mean total treatment time was 4.06±1.11 vs 1.26± 0.47 weeks (P<0.01), the mean hospital stay after procedure was 3.66 ± 1.29 vs 5.13 ± 0.43 days (P<0.01), and the mean total medical cost was ￥54 291.00±6149.00 vs ￥23 482.00±2317.00 (P<0.01), respectively. Conclusion FURS is safe and effective for treatment of renal stones of 2-4 cm in diameter, and a staged procedure is necessary to achieve a stone-free status for large calculi. Both sophisticated equipment and rich surgical experience are essential to ensure treatment success.