Although the impact of comorbidity on outcomes in ESRD has been evaluated extensively, its contribution after kidney transplantation has not been well studied. It is believed that comorbidity assessment is critical to the informed interpretation of kidney transplant outcomes. In this study, the Charlson Comorbidity Index was used to assess the comorbid conditions of 715 patients who underwent kidney transplantation at the Starzl Transplant Institute between January 1998 and January 2003. The impact of pretransplantation comorbidity on the development of acute cellular rejection after transplantation and on patient and graft survival was examined. The most common comorbid conditions among our patient population were diabetes (n = 217, 30.3%) and heart failure (n = 85, 11.9%). It was found the number of patients with high comorbidity at the Starzl Transplant Institute has increased significantly over time (P = 0.04). In multivariate adjusted models, high comorbidity was associated with an increased risk for patient death, both in the perioperative period (hazard ratio 3.20, 95% confidence interval 1.32 to 7.78; P = 0.01) and >3 mo after transplantation (hazard ratio 2.63; 95% confidence interval 1.62 to 4.28; P < 0.001). The Charlson Comorbidity Index is a practical tool for the evaluation of comorbidity in the transplant population, which has an increasing burden of comorbid disease. Increased comorbidity affects both perioperative and long-term patient outcomes and carries significant implications not only for the development of individual patient therapeutic strategies but also for the interpretation of patient trials and the development of policies that govern distribution of donor organs.