Background: The advent of immune checkpoint inhibitors (ICIs) has revolutionized the metastatic renal cell carcinoma (mRCC) therapeutic landscape. Nevertheless, tyrosine-kinase inhibitors (TKIs) targeting the vascular endothelial growth factor (VEGF) axis still play a key role. The aim of the present study was to explore the prognostic performance of an integrated blood score, based on hemoglobin (Hb) concentration, mean corpuscular volume (MCV), and red cell distribution width (RDW), in mRCC patients treated with anti-VEGF TKIs. The primary endpoint was to correlate Hb, MCV, and RDW with progression-free survival (PFS) and overall survival (OS). Materials and Methods: Our multicenter retrospective observational study involved mRCC patients treated with pazopanib or cabozantinib from January 2012 to December 2020 in nine Italian centers. Clinical records and laboratory data, including Hb levels, MCV, and RDW, were collected at baseline. Descriptive statistics and univariate and multivariate analyses were performed. Results: We enrolled 301 mRCC patients of which 179 (59%) underwent pazopanib, and 122 (41%) cabozantinib. We considered baseline Hb \ge12 g/dL, MCV >87 fL, and RDW \le16% as good prognostic factors; hence, developing a multiparametric score capable of delineating 4 different categories. The number of good prognostic factors was associated with significantly longer PFS and OS (p 0.001 for both). Therefore, we developed a red blood cell-based score by stratifying cases into two groups (2–3 versus 0–1, good factors). The impact on PFS and OS was even more striking (median PFS (mPFS): 16.3 vs 7.9 months; median OS (mOS): 33.7 vs 14.1 months)), regardless of the TKI agent. When challenged with univariate and multivariate analysis, the blood score maintained its high prognostic significance in terms of OS (multivariate analysis HR for OS: 0.53, 95% CI 0.39–0.75; p 0.001, respectively), while the impact on PFS resulted in borderline significance. Conclusions: Our analyses demonstrate the prognostic role of a multiparametric score based on easily exploitable blood parameters, such as Hb concentration, MCV, and RDW. The red blood cell-based score may underlie the upregulation of the HIF-1\alpha pathway and VEGF axis, thereby identifying a selected population who is likely to benefit from TKI therapy.