Objective This study aimed to compare the effect of percutaneous nephrolithotomy (PCNL) under local infiltration anesthesia (PCNL-LIA) and general anesthesia (PCNL-GA) to treat upper urinary tract calculi on clinical application values. Methods Patients were randomly divided into the PCNL-LIA (16 patients) and PCNL-GA (20 patients) groups. Data on safety, cost, complications, rate of residual calculi, and prognosis were compared. Results The mean operation time in the PCNL-LIA group was less than that in PCNL-GA group (100±7.7 versus 120±9.0 minutes). The mean length of hospital stay in the PCNL-LIA group was shorter than that in the PCNL-GA group (6.9±0.5 versus 10.5±1.2 days). The rate of patients who required blood transfusion because of blood loss during or after surgery was less in the PCNL-LIN group than in the PCNL-GA group (13% versus 40%). The intervention rate in the PCNL-GA group was higher than that in the PCNL-LIA group. Visual analogue pain scale assessment showed that the PCNL-LIA group showed slightly more pain than the PCNL-GA group. Conclusion PCNL-LIA is safer, faster, and more convenient, and it also provides the benefits of a lower rate of blood loss and complications, lower cost, faster recovery, and shorter hospital stay compared with PCNL-GA.