Background: Bone-predominant metastatic renal cell carcinoma (mRCC) is associated with aggressive biology and poor prognosis. The optimal management of these patients (pts) remains not well-established. While contemporary trials showed the superiority of immune checkpoint inhibitors (ICI) compared to vascular endothelial growth factor tyrosine kinase inhibitors (TKI), these pts were often excluded due to non-measurable disease. mRCC bone metastases show an enhanced angiogenesis gene signature suggesting the potential for greater responses to TKI. We test this hypothesis in a retrospective study comparing treatment outcomes for the first line (1L) TKI versus ICI in pts with bone-predominant mRCC. Methods: Pts with mRCC who received care at the Ohio State University Comprehensive Cancer Center from 1/1/2008 to 6/1/2021 were identified through retrospective chart review. Bone-predominant metastasis was defined as the number of bone metastases > extra-osseous metastases. Pts who had ≥1 cycle of treatment and follow-up scans were evaluated for treatment responses per RECIST 1.1 criteria. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. The comparisons were made between TKI and ICI cohorts, and the significance was determined by logrank test. Pt who received ICI-TKI in 1L were excluded from the survival analysis due to limited N. Results: A total of 335 pts with mRCC were identified, of which 45 (13.4%) had bone-predominant metastasis. Most of the pts (44/45) had clear cell histology. TKI was the 1L intervention for 21 (47%) while 20 (44%) pts received ICI, and 4 (9%) pts received TKI-ICI. TKI and ICI cohorts were similar for International Metastatic RCC Database Consortium (IMDC) Risk (Table). In the TKI cohort, 19 pts had evaluable responses with ORR of 15.7% and SD of 42%. The mPFS was 5.9 months (95% CI 2.8–9), and mOS was 30.4 months (95% CI 3.3–57.6). In the ICI cohort, 16 had evaluable responses with ORR of 6% and SD of 43.8%. The mPFS was 3.4 months (95% CI 0–8.2), and mOS was 19.3 months (95% CI 14.9–23.7). The hazard ratio was 0.58 for PFS and 0.54 for OS, favoring TKI over ICI, although statistical significance was not reached due to the small sample size (p=0.10 and 0.12, respectively). Conclusions: In this single-center retrospective study, pts with bone-predominant mRCC who received TKI compared to ICI as 1L therapy showed improved ORR, PFS, and OS. These results warrant further investigation in larger studies comparing TKI-containing regimen vs ICI doublet.