The identification of prognostic factors in patients with renal cell carcinoma (RCC) represents an area of increasing interest. In this retrospective study, we evaluated the prognostic role of carbonic anhydrase-IX, ezrin, and neuropilin in metastatic RCC patients. The expression of several biomarkers were measured by immunohistochemistry (IHC) in 45 patients with advanced stage RCC treated with second-line tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) after failure of interferon-alpha between January 2007 and June 2012. Kaplan-Meier curves and log-rank tests were used for analysis of progression-free survival (PFS) and overall survival (OS), and a multivariate Cox proportional hazard model was employed to identify factors with an independent effect on the survival. Age, ezrin and neuropilin-2 overexpression were found to be statistically significant factors (P < 0.05) for PFS in the univariate analysis. Ezrin and neuropilin-2 overexpression, hemoglobin and albumin level were statistically significant factors (P < 0.05) for OS in the univariate analysis. Multivariate analysis revealed that low expression of ezrin and neuropilin-2 was an independent prognostic factor for PFS and OS. The median PFS was 4 months for patients overexpressing neuropilin-2 versus 11 months for those with lower expression of neuropilin-2 (p = 0.033). The median OS was longer in patients with low levels of neuropilin-2 expression (26 months) compared to patients overexpressing neuropilin-2 (13 months) (p = 0.023). Increased expression of ezrin was associated with poor prognosis in patients treated with TKIs targeting VEGF (PFS, 3 vs 7 months; p = 0.012). High ezrin expression was associated with shorter OS (p = 0.009). This is the first study in the literature showing that neuropilin-2 and ezrin are related with prognosis in patients with advanced RCC.