To assess the safety and efficacy of minimally invasive percutaneous nephrolithotomy (mPCNL) as compared to standard PCNL (sPCNL) for management of 2–3-cm renal stones in the flank-free modified supine position. Between September 2010 and December 2013, 150 patients (168 renal units) with 2–3-cm renal stones were prospectively randomized into two treatment groups; Group A (75 patients/87 renal units) treated by mPCNL and Group B (75 patients/81 renal units) treated by sPCNL. In both groups, the patients were placed in the flank-free modified supine position. In mPCNL group, the tract was dilated up to 16.5 F whereas in sPCNL group the tract was dilated up to 30 F. Both groups were compared regarding several perioperative parameters. No significant difference was recorded among both groups regarding fluoroscopy time (4.3 ± 1.3 vs 4.8 ± 2.1 min, p = 0.06), operative time (83.2 ± 17.3 vs 78.6 ± 24.4 min, p = 0.16), hospital stay (4.3 vs 4.5 days, p = 0.76), VAS score (3.2 ± 0.6 vs 3.3 ± 0.8, p = 0.36) and need for analgesia. The mean drop in hemoglobin level and the incidence of bleeding that necessitated blood transfusion were significantly lower in the mPCNL group (0.6 ± 0.1 vs 1.9 ± 1.1 g/dl, p < 0.0001 and 1.2 vs 9.8%, p = 0.03, respectively). Although the stone-free rate was higher in the sPCNL group, but this was statistically insignificant (97.1 vs 95.4%, p = 0.86). Mini-PCNL is effective for managing renal calculi with comparable operative time and stone-free rate to standard PCNL with the merit of higher safety due to lower incidence of bleeding that necessitates blood transfusion.