Purpose <p>Combinations of anti-PD-1/PD-L1 immunotherapy (IO) and anti-VEGF tyrosine kinase inhibitor (TKI) are recommended as first-line therapy for metastatic renal cell carcinoma (RCC). We aimed to evaluate the predictive value of tissue factor pathway inhibitor 2 (TFPI2) for IO + TKI response.</p> Methods <p>TFPI2 expression and its association with IO + TKI response and progression-free survival (PFS) were analyzed in the ZS-MRCC and JAVELIN Renal 101 cohorts. Tumor microenvironment analyses were conducted in ZS-HRRCC and TCGA-KIRC cohorts using RNA-sequencing, flow cytometry, immunohistochemistry, and immunofluorescence.</p> Results <p>TFPI2 expression was elevated in IO + TKI non-responders (<i>p</i> = 0.044) and predicted shorter PFS in ZS-MRCC (<i>p</i> = 0.026) and JAVELIN Renal 101 (<i>p</i> = 0.007) cohorts. Multivariate analysis confirmed TFPI2 as an independent prognostic factor (HR = 2.42; <i>p</i> = 0.030). High-TFPI2 tumors exhibited reduced Granzyme B⁺CD8⁺ (<i>p</i> = 0.05) and Granzyme B⁺CD4⁺ (<i>p</i> = 0.02) T cell infiltration, with elevated exhaustion markers including TIGIT (<i>p</i> = 0.039), CTLA4 (<i>p</i> = 0.021), EOMES (<i>p</i> = 0.047), and TCF1 (<i>p</i> = 0.034), a marker of progenitor exhausted T cells (Tpex). A random forest model integrating TFPI2 and immune-related genes stratified IO + TKI benefit: the RF score-low group derived significant benefit from IO + TKI (HR = 0.477; 95% CI: 0.354–0.644), whereas the RF score-high group did not (HR = 0.936; 95% CI: 0.692–1.265, <i>p</i> for interaction = 0.001).</p> Conclusion <p>TFPI2 overexpression is associated with immune evasion and poor PFS in RCC patients treated with IO + TKI. The RF model may facilitate precision treatment selection between IO + TKI and TKI monotherapy.</p>