Background: A previously created and analyzed composite renal cell carcinoma (RCC) inflammatory score composed of preoperative serum markers was found to be a significant and independent predictor of overall survival in RCC with accuracy at least as good as other established prognostic tools. The aim of our study was therefore to validate the prognostic significance of this novel score in a new, independent cohort of localized clear cell RCC patients. Methods: A new cohort was randomly selected out of our nephrectomy database from a group of patients with localized clear cell RCC, who underwent nephrectomy from March 2007 to June 2017. Biomarker composition, cutoffs, and calculations of the RCC inflammatory score were accurately recreated from the previous publication. The final score was the sum of points accrued for each biomarker, ranging from 0-10, followed by stratification into baseline (0), low (1-3), intermediate (4-6), and high-risk (7-10) groups. ROC and chi-square analysis were performed to compare the prognostic ability of this novel score to SSIGN, UISS, mGPS, and Leibovich Scores. Impact on overall survival was analyzed with multivariate logistic regression analysis. Results: 252 patients were included in the study. On multivariate analysis, after adjusting for confounding variables, a “high-risk” RCC inflammatory score proved to be an independent and significant predictor of increased mortality (HR = 9.65, 95%CI 1.06-87.79, p = 0.044). At median follow up time, only 45% of high-risk score patients were alive compared with 89-98% of all other patients. Chi-square analysis of c-indices for the RCC inflammatory score and current prognostic scores revealed no statistically significant difference in prognostication of overall survival. Conclusions: Concordant with our previous data, this study reveals that a high-risk RCC inflammatory score is an independent and significant predictor of overall survival in localized clear cell RCC with comparable accuracy to accepted prognostic tools. Distinct from the original study, the high-risk group displayed an even greater association than previously shown, but the intermediate-risk group was no longer significantly different from baseline risk.