Background: There are currently no RCC biomarkers being routinely used in the clinic, and prognostic nomograms rely almost entirely on tumor size, stage and age. There is a critical need for improved prognostic discrimination given the increasing awareness that some patients may be managed with active surveillance, while others with higher risk disease might benefit from adjuvant therapy following surgery. We hypothesized that a previously developed multi-gene proliferation signature would predict long-term oncologic outcomes in surgically resected RCC. Methods: The cell cycle proliferation (CCP) score was derived after radical nephrectomy in 305 patients who were treated at a single center from 2000 to 2007 for clear cell, papillary or chromophobe RCC with localized disease (N0M0). Sixty-four percent of the cohort had stage I disease. Outcomes were either disease recurrence (local or metastatic), or disease specific mortality (DSM). Association with outcomes was evaluated by CoxPH survival analysis and likelihood ratio tests. Hazard ratios (HR) are given for one-unit increase in CCP score (equivalent to a doubling of gene expression). Results: Patient data were censored at 5-years of follow-up, by which time 32 patients (10%) recurred and 16 (5%) died of disease. The median CCP score was 0.095 (IQR -0.50 to 0.60). In univariable analysis, CCP score was a significant prognostic variable for both recurrence (p < 10^-4) and DSM (p < 10^-5). After adjusting for clinical variables including tumor size, stage, and grade, the CCP score HR for recurrence was 1.74 (95% CI (1.14, 2.65)), and for DSM was 2.59 (95% CI (1.43, 4.67)). There was no interaction between CCP and any clinical variable. A prognostic model combining clinical and molecular information will be presented along with external validation in a second cohort (N~400). Conclusions: The CCP score appears to be a significant and independent predictor of key long-term oncologic outcomes in patients who have undergone nephrectomy for RCC, providing prognostic information beyond what is available from clinical parameters. Once validated, the CCP score may have utility in the clinical management of patients with RCC.