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Background: Percutaneous nephrolithotomy (PCNL) is the most common surgical procedure for the removal of renal stone of size >2 cm. It has evolved over the years both in terms of surgical technique and plan of anesthesia. The procedure is performed most commonly in the prone position. This position provides edge in offering greater anatomical feasibility due to the posterior retroperitoneal position of kidneys. Supine position bestows several perks over prone in terms of better access to patient's airway, lower cardiopulmonary complications, better patient comfort, repositioning issues addressal along with convenient access to the patient by anesthesiologist in case of untoward medical emergency. Aims and Objectives: The primary aim to compare the safety and efficacy of prone versus supine PCNL. The objective was to compare the two techniques in terms of Visual Analog Scale Score, patient satisfaction rate, stone-free rate, procedure time (calculated from placement of ureteric catheter to skin closure), overall complication rate. Materials and Methods: This prospective randomized study of 80 patients was conducted at our institute from December 2022 to June 2023. Institutional Ethical Committee clearance was sought and the inclusion criteria were all adult patients aged between 16 and 65 years with single renal, upper ureteric calculus of size 10-25 mm with ASA physical status 1 and 2 having normal renal function and a sterile urine culture. Results: All the patients completed the study and there were no dropouts. Male/female ratio, age, and stone size were comparable in both the groups. The mean time taken in supine PCNL was 48.3 min and in prone PCNL was 68.7 min, which was significant. Conclusion: Supine PCNL is a safe and efficacious procedure for renal stone disease in the selected group of patients with results comparable to prone PCNL, having additional advantages like less time-consuming, better upper calyceal access through lower calyx, less radiation exposure to surgeon's hand, overcoming positional difficulties of prone position, simultaneous accessibility for performing flexible ureteroscopy and more convenient airway access to anesthesiologist and better pain scores. [ABSTRACT FROM AUTHOR]