Objectives: Although the classification of cancer has traditionally focused on the gross and microscopic characteristics of the tumor, the overall health of patients can affect their survival. Because patients with renal cell carcinoma often have other medical conditions, we explored the effect of preexisting medical disease on survival after radical and partial nephrectomy. Methods: From January 1995 to August 2003, the comorbidity status of 697 patients with nonmetastatic renal cell carcinoma who had undergone radical or partial nephrectomy was prospectively coded using the Adult Comorbidity Evaluation-27. Histopathologic review of all slides was performed according to the 2004 World Health Organization scheme. Other variables analyzed included age, sex, ethnicity, pathologic stage, Fuhrman grade, and tumor size. The effect of these factors on overall survival (OS) was analyzed using Cox proportional hazards regression model. Results: The median follow-up was 32.2 months for survivors and 36.5 months for all patients. The OS rate at 1, 3, and 5 years was 92.0% (641 patients), 75.3% (525 patients), and 52.7% (367 patients), respectively. Univariate analyses demonstrated that age, comorbidity, tumor size, Fuhrman grade, and pathologic stage were significant predictors of OS. Multivariate analysis revealed that age (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.10 to 1.82, P = .0067), comorbidity (HR 1.37, 95% CI 1.16 to 1.63, P = .0002), pathologic stage (HR 1.97, 95% CI 1.60 to 2.41, P < .0001), and grade (HR 1.83, 95% CI 1.28 to 2.59, P = .0008) predicted for OS. Conclusions: The results of this study have demonstrated that comorbidity is an independent prognostic factor for OS in patients with renal cell carcinoma. Capturing the comorbidity information using validated instruments can improve the preoperative evaluation of patients by providing more accurate prognostic information.