AIM: The indications for performing retrograde intrarenal surgery (RIRS) have increased. However, no comparative studies have been conducted on the treatment of staghorn renal calculi using RIRS and percutaneous nephrolithotomy (PCNL). We aimed to compare the effectiveness and safety of RIRS and PCNL as treatments for staghorn renal calculi. METHODS: We conducted a retrospective analysis of patients with staghorn renal calculi who underwent either PCNL or RIRS at our hospital from January 2021 to July 2023. Patients with staghorn renal calculi and renal malformation, as well as those with interrupted treatment or irregular follow-up, were excluded from the study. We compared the perioperative outcomes and complications between the groups. RESULTS: Fifty patients were included in the RIRS group, whereas 48 patients were included in the PCNL group. 1. No significant differences were observed between the groups regarding the number of complete staghorn calculi, stone size, age, sex, or other demographic characteristics. 2. RIRS was associated with a shorter postoperative hospitalization time (2.14 ± 0.76 vs. 5.15 ± 1.98 days, p < 0.001). 3. RIRS was associated with a decrease in hemoglobin (0.1 [0, 0.2] vs. 0.65 [0.4, 1] g/dL, p < 0.001) and a lower pain score (1 [1, 2] vs. 2 [1, 3], p = 0.008). 4. Compared with PCNL, RIRS did not significantly differ in terms of the 1-stage stone-free rate (50% vs. 66.67%, p = 0.095) or total stone-free rate (84% vs. 89.58%, p = 0.415). 5. The overall complication rate was lower in the RIRS group (10% vs. 16.67%, p = 0.331). CONCLUSIONS: Compared with PCNL, RIRS can reduce bleeding and overall complications, shorten the hospitalization time, and achieve satisfactory stone-free rate. As a result, RIRS can be considered an alternative treatment option for staghorn renal calculi.