OBJECTIVE The percutaneous nephrolithotomy (PCNL) has become the gold-standard for treating patients with the larger renal stones and staghorn calculi. This study was designed to evaluate the outcomes of flank versus prone position in patients underwent ultrasonic-guided PCNL for treatment of large kidney stones. METHODS This prospective randomized clinical trial was conducted from September 2017 to September 2019 in the department of Urology, Labbafinejad University hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. Two hundred patients with kidney stones larger than 2 cm underwent PCNLs in prone (n = 100) or flank position (n = 100). Success rate, operative time, access time, hemoglobin and creatinine changes, hospital stay, auxiliary procedure and surgical complications were compared between the two groups. RESULTS The two groups were similar in their baseline characteristics. The success rates in prone (87%) versus flank position (85%) were not significantly different at the first post-operative follow-up (p = 0.91). At the three-month follow-up, the overall stone free rates for the prone position PCNLs and flank position PCNLs were 94/100 (94%) and 90/100 (90%) (p = 0.96). There were no significant difference between the groups in operative time (p = 0.42), access time (p = 0.66), hemoglobin (p = 0.46) and creatinine (p = 0.22) changes, hospital stay (p = 0.05), auxiliary procedures (p = 0.75) and surgical complications. CONCLUSIONS Overall, there is no significant difference between prone and flank positions in success rate and complications. More prospective studies must be carried out to identify patient populations who are most apt to benefit from one position over the other. BACKGROUND IRCT20200902048597N1 DATE OF REGISTRATION: 2020-11-21, retrospectively registered.