OBJECTIVE: Percutaneous nephrolithotomy (PCNL) is a common endourological procedure for patients with large kidney stones, but the management of postoperative pain is still a major challenge. The aim of this clinical trial was to evaluate the efficacy of 0.25% bupivacaine infiltration along the nephrostomy tract on postoperative pain scores and analgesia consumption in patients who underwent PCNL. PATIENTS AND METHODS: A total of 50 patients who underwent PCNL were enrolled in this prospective, randomized controlled trial (NCT04160936). Patients were prospectively randomized into two equal groups: the study group (n=25) received 20 mL of 0.25% bupivacaine infiltration along the nephrostomy tract, whereas patients in the control group (n=25) did not. Postoperative pain as the primary outcome was assessed by using a visual analogue scale (VAS) and a dynamic visual analogue scale (DVAS) at different time points. The secondary outcomes were the time for first opioid demands, the number of opioid demands, and the total opioid consumption over the 48 h postoperatively. RESULTS: There were no significant differences between the two groups regarding demographics, surgery, and stone characteristics. Patients in the study group had significantly less VAS and DVAS pain scores compared to the control group. The mean time of the first opioid demand in the study group was significantly longer as compared to the control group (7.1 ± 2.5h vs. 3.2 ± 1.8 h, p<0.001). The mean number of doses and total consumption of opioids were significantly less in the study group compared to the control group over 48 h (1.5 ± 0.8 vs. 2.9 ± 0.7 and 122.82 ± 62.5 mg vs. 223 ± 70 mg, respectively) (p<0.0001). CONCLUSIONS: Local anesthetic infiltration of 0.25% bupivacaine along the nephrostomy tract is efficient in alleviating post-operative pain and reducing opioid consumption after PCNL.