Objective <p>To evaluate the efficacy and safety of endoscopic combined intrarenal surgery (ECIRS) in the Galdakao-Modified Supine Valdivia (GMSV) position versus percutaneous nephrolithotomy (PCNL) in the prone position for managing complex kidney stones.</p> Methods <p>This prospective, randomized study was conducted in the urology departments of Benha University Hospital and Theodor Bilharz Research Institute between June 2021 and May 2024. A total of 60 patients with complex renal stones were randomly assigned to two groups (30 patients each). Group A underwent conventional percutaneous nephrolithotomy (PCNL) in the prone position, while Group B underwent endoscopic combined intrarenal surgery (ECIRS) in the Galdakao-Modified Supine Valdivia (GMSV) position. Data on demographic characteristics, clinical outcomes, perioperative parameters, and stone-free rates (SFR) were collected.</p> Results <p>No significant differences were found between the two groups regarding preoperative demographic data and stone characteristics. However, operative time was significantly longer in the PCNL group (119 ± 18 min) compared to the ECIRS group (105 ± 14 min) (<i>P</i> = 0.002). The number of punctures was also significantly higher in the PCNL group than in the ECIRS group (<i>P</i> = 0.001). Immediate success was notably higher in the ECIRS group (83.3%) compared to the PCNL group (53.3%) (<i>P</i> = 0.012). However, no significant difference was observed between the groups concerning eventual success (<i>P</i> = 1.0).</p> Conclusion <p>ECIRS is a highly effective treatment for complex renal stones, delivering favorable outcomes such as higher single-step stone-free rates, a lower incidence of adverse events, and a reduced need for auxiliary procedures.</p>