There is a lack of consensus among transplant physicians regarding the optimal management of the large number of patients who return to dialysis (approximately 2000 per year) with a failed kidney transplant (1–3). The high rate of morbidity and mortality experienced by patients after primary kidney transplant failure exceeds those observed in dialysis patients who are awaiting kidney transplantation (4–7). Dialysis patients with failed previous transplants have been shown to have a standardized mortality ratio of 1.35 compared with dialysis patients who have never received a renal transplant (8). Several predictors of patient survival after allograft failure have been identified, such as age, diabetes, HLA matching, gender, and first transplant donor type (1,9). Mortality after primary allograft failure is strongly influenced by the type of ESRD, the highest rate found among patients with type 1 diabetes compared with either type 2 diabetes or other causes of ESRD (1). The reasons for the poor survival after graft failure have remained elusive. The triggering of an inflammatory process by the retained allograft (characterized by hypoalbuminemia, erythropoietin resistance, high ferritin, and elevated C-reactive protein) and an increased incidence of infectious and cardiac complications as a result of ongoing immunosuppression have been observed but not yet confirmed by controlled clinical studies (10–12). The goal of this observational study was to evaluate the impact of transplant nephrectomy on the survival of patients who return to dialysis after kidney transplant failure. Using the US Renal Data System, the authors identified and analyzed a cohort of patients (n = 10,951) who returned to dialysis (hemodialysis and peritoneal dialysis) during a 10-year period spanning from January 1994 through December 2004. Findings. Thirty-one percent (n = 3451) of the study cohort underwent a transplant nephrectomy during the study period. The procedure was associated with a 32% lower adjusted relative mortality risk (adjusted hazard ratio 0.68; 95% confidence interval 0.63 to 0.74). The median time between the return to dialysis and nephrectomy was 1.66 years (interquartile range 0.73 to 3.02). The group that underwent a nephrectomy was composed of younger individuals who were less likely to have diabetes and/or cardiovascular disease (congestive heart failure and cerebrovascular and peripheral vascular disease). These patients were more likely to be black; to have required the use of T cell–depleting antibodies (thymoglobulin, OKT3); and to have experienced anemia, sepsis, and urinary tract infections. Despite these complications, the rate of death within 30 days of the transplant nephrectomy was only 1.5% (53 deaths of 3451 patients). Lastly, they were more likely (10 versus 4.1%; P < 0.001) to receive a second transplant when compared with those who did not undergo a nephrectomy. Commentary. The long-held clear-cut indications for transplant nephrectomy are fever, infection, hematuria, and a painful allograft. Most of these symptoms are the result of rejection and/or allograft ischemia (venous and arterial thrombosis). The increased morbidity and mortality (range 6 to 37%) associated with the nephrectomy of a failed allograft are undisputed (13,14). Conversely, no consensus has been reached regarding the effects of either early or late allograft nephrectomy on repeated renal transplant survival (15–17) and/or alloimmunity (18–20). The retrospective, observational analysis provided by Ayus et al. is insightful and suggests that the traditional indications for failed allograft nephrectomies may be in need of revision. The patient and future renal transplant survival outcomes after nephrectomy for graft-related symptoms are probably different from those observed when the procedure is done electively. No information regarding the indication for the procedure and/or the type of prescribed immunosuppression is provided in this study. If the need for nephrectomy were triggered by an immune event (e.g., humoral rejection), then the procedure may just be a marker of high immune responsiveness and an indication of an adverse outcome with repeated transplantation (i.e., selection bias). The study design (observational analysis of administrative data) does not permit a random selection of allograft nephrectomy and represents a potential source of bias, although the authors did apply a series of adjustments such as sensitivity analyses and propensity scores to try to minimize this effect; however, as noted by the authors, the most convincing evidence for the role of transplant nephrectomy in asymptomatic patients remains to be investigated in prospective, randomized clinical studies.