Background: To evaluate the effect of tumor burden on survival in patients with metastatic renal cell carcinoma who are administered sequential molecular-targeted therapy. Methods: A total of 68 patients were recruited. Baseline tumor burden at the time of second-line therapy initiation was calculated according to the Response Evaluation Criteria in Solid Tumors v.1.1.Patients were divided into two subgroups according to the median tumor burden: greater than the median as the high group, lower than the median as the low group. Progression-free survival and overall survival after second-line therapy were analyzed. The effect of tumor burden changes on survival during sequential targeted therapy were also evaluated. Results: Median second-line tumor burden was 57.7 cm. The patients with high tumor burden had significantly poorer progression-free survival and overall survival, compared to those with low tumor burden ( median progression- free survival = 4.36 vs. 8.19 months, P = 0.0119; overall survival = 9.6 vs. 23.5 months, P = 0.0107). For progression- free survival, multivariate analyses revealed that second-line objective response was an independent predictor ( P < 0.0001), but second-line tumor burden was not ( P = 0.0826). For overall survival, second-line tumor burden and objective response were independent predictors ( P = 0.0300 and < 0.0001, respectively). Moreover, there was a positive correlation between first-and second-line tumor burden ( r(2) = 0.460, P < 0.0001), although tumor burden changes between first-and second-line therapies did not affect survival ( median progressionfree survival, P = 0.812; overall survival, P = 0.415). Conclusions: Second-line tumor burden was an independent predictor of overall survival among patients with metastatic renal cell carcinoma after second-line therapy.