Background: During the last ten years, several classifications have been used to assess the prognosis in mRCC. In none of them, tumor burden (TB) has been considered. This study investigates the prognostic role of baseline TB in terms of progression free survival (PFS) and overall survival (OS), in patients with mRCC. Methods: All patients with clear cell mRCC enrolled in our center, in 2 second-line trials, post cytokine, with sunitinib and sorafenib or placebo (Escudier JCO 2009, Escudier NEJM 2007), were selected for this analysis. TB was defined as the sum of the longest unidimensional diameter of each target lesions assessed using RECIST criteria. PFS and OS were estimated using Kaplan-Meier method and compared using the log-rank test. Association between TB and PFS or OS was evaluated using the Cox proportional hazards model. Multivariable analyses were adjusted for modified MSKCC risk class and treatment. Non-parametric Spearman rank test (r_s) was used to assess the correlations between TB and MSKCC risk groups or ECOG Performance Status (PS). Results: Final population included 124 patients: 66% received sorafenib or sunitinib and 34% received placebo; median follow up was 80.1 months (IQR: 68.8 – 88.0). Baseline TB was divided into 3 tertiles (1.3 - 9.4 cm; 9.5 - 19.0 cm; 19.1 - 47.3 cm). TB was related to PFS and OS and, when adjusting for modified MSKCC risk class and treatment, these associations remained significant: each 1 cm increase in TB increased the progression risk by 5% (HR: 1.05; 95%CI, 1.02 – 1.07; p < 0.0001) and the death risk by 5% (HR: 1.05; 95%CI, 1.03 – 1.08; p < 0.0001). OS decreased with TB: the median tertiles OS values were: 42.1 months (95%CI: 24.0 – 60.2), 20.1 months (95%CI: 14.5 – 25.7), and 11.2 months (95%CI: 4.8 – 17.6), respectively (p < 0.0001, figure 2). The TB was positively related to ECOG PS (r_s = 0.357; p < 0.0001) and to MSKCC risk score (r_s = 0.478; p < 0.0001). Patients with higher TB had shorter PFS, shorter OS, poorer MSKCC score and increased ECOG PS. Conclusions: TB is easy to calculate with standard CT and significantly relates to OS and PFS in patients with mRCC. We report for the first time the independent prognostic role of baseline TB in mRCC.