Objective To systematically compare the clinical efficacy between percutaneous nephrostomy （PCN） and indwelling ureteral stent （US） for renal pelvis decompression in patients with upper urinary tract stones complicated with urogenic sepsis. Methods From January 2020 to December 2022, 80 patients with upper urinary tract stones complicated with urosepsis admitted to our hospital were selected. According to a random number table, they were randomly divided into a PCN group （40 cases） and a US group （40 cases）. The infection control [including the success rate of renal pelvic decompression, the recovery time for body temperature, white blood cell count, and C-reactive protein （CRP）, the length of hospital stay for infection control, the infection progression rate within 30 min postoperatively, and the ureter/renal pelvis perforation rate] and the effectiveness of two-stage lithotripsy （including surgery time, flexible scope usage rate, stone clearance rate, and postoperative fever rate） were compared between the two groups （stratified by whether shock was present or not）. Results Compared with the non-shock patients in the US group, the non-shock patients in the PCN group had a higher success rate of renal pelvic decompression, a faster recovery of body temperature, white blood cell count, and CRP, as well as shorter hospitalization days for infection control （P<0.05）; there was no statistically significant difference in infection progression and ureter/renal pelvis perforation rates 30 min after surgery （P>0.05）. Compared with the shock patients in the US group, the shock patients in the PCN group showed comparable success rate of renal pelvic decompression （P>0.05）, and faster recovery of body temperature, white blood cell count, and CRP, and shorter hospitalization days （P<0.05）; there was no statistically significant difference in infection progression rate 30 min after surgery （P>0.05）; no perforation occurred. Regarding the effect of two-stage lithotripsy, the PCN group had less surgery time, use of flexible scope, and postoperative fever, and a higher stone clearance rate than the US group （P<0.05）. Conclusion In the treatment of urinary tract stones combined with urogenic sepsis, PCN has a higher success rate of renal pelvis decompression, faster infection control, and higher efficiency and safety of two-stage lithotripsy, which is worthy of clinical priority recommendation.