Study Type--Prognosis (cohort series) Level of Evidence 2b. What's known on the subject? and What does the study add? In the literature, few studies have evaluated the role of tumour burden (TB) in metastatic real cell carcinoma (mRCC), even though it has been considered as important in localized tumours. In metastatic patients the role of TB is uncertain because it was analyzed in chemotherapy treated patients or using a partial evaluation of TB. This study, first reports the independent prognostic and predictive role of TB in mRCC patients treated with targeted agents in prospective clinical trials. TB is able to predict prognosis independently to localization of metastases and prognostic class defined by MSKCC criteria, moreover it is strictly related to patient's performance status. OBJECTIVE • To investigate the possible prognostic role of baseline tumour burden (TB) in terms of progression-free survival (PFS) and overall survival (OS), in patients with metastatic renal cell carcinoma (mRCC). METHODS • A homogenous group of patients with mRCC enrolled in second-line trials post-cytokine treatment were selected for the present analysis. • The Response Evaluation Criteria in Solid Tumors (the sum of the longest unidimensional diameter of each target lesion) were used to assess TB. • The PFS and OS rates were estimated using the Kaplan-Meier method and compared across the groups using the log-rank test. • The association between TB and PFS or OS was evaluated using a Cox proportional hazards model. Multivariable analyses were adjusted for other prognostic variables: the Memorial Sloan Kettering Cancer Centre (MSKCC) risk class and treatment. RESULTS • A total of 124 patients were included in the final analysis. Of these, 66% received sorafenib or sunitinib and 34% received placebo. The median follow-up was 80.1 month. • TB was directly related to PFS and OS and these associations remained significant after adjusting for modified MSKCC risk class and treatment,. • Each 1-cm increase in TB increased the risk of progression by 4.5% (hazard ratio [HR]: 1.05; 95% confidence interval [CI] 1.02-1.07; P < 0.001) and the risk of death by 5% (HR: 1.05; 95% CI 1.03-1.08; P < 0.001). CONCLUSIONS • TB is easy to calculate from standard computed tomography and significantly relates to OS in patients with mRCC. • We report for the first time the independent prognostic role of baseline TB in multivariate analysis. •  We believe that this information could be translated into clinical practice.