Objectives. To determine by retrospective review of 315 percutaneous nephrostomies, performed for pyonephrosis, whether this intervention has major clinical advantages. Methods. From 1977 to 1996, under the direct supervision of the senior author of this report (E.K.L.), at seven hospital sites, 315 patients (181 males, 134 females; 17 to 88 years of age) were treated with percutaneous nephrostomy and antibiotic therapy for infected hydronephrosis. Results. Additional or disparate pathogens were identified in 116 (36.8%) of 315 patients, leading to a clinically significant change in, or addition of, antibiotics and/or antifungal agents in 84 (73%) of 116. Most notably, we often found a clinically important disparity between the results of cultures obtained from the nephrostomy and those obtained from bladder-urine specimens. Conclusions. This retrospective review confirms previously reported advantages of percutaneous upper urinary tract drainage as a potentially life-saving adjunct in the treatment of pyonephrosis. Several case studies highlight the advantage of this maneuver in difficult cases involving obstruction due to extensive fungus or debris. In particular, our review focuses attention on the clinically important insight that urine cultures from percutaneous nephrostomy drainage often identify pathogens that differ from those detected in concurrent bladder cultures.