BACKGROUND: Immuno-oncology (IO) combination therapies, including IO + IO or IO + vascular endothelial growth factor targeted therapies (VEGF-TT), have become the standard first-line treatment for advanced renal cell carcinoma (RCC). However, the optimal regimen for patients without prior nephrectomy remains unclear. METHODS: Data from 99 patients with advanced RCC without nephrectomy, treated with VEGF-TT, IO + IO, or IO + VEGF-TT between May 2008 and May 2024, were retrospectively reviewed and analyzed. Patients were divided into VEGE-TT, IO + IO, and IO + VEGF-TT groups based on their first-line treatment, and survival and tumor response were compared. RESULTS: All patients included in this study were categorized as either intermediate or poor risk according to the International Metastatic RCC Database Consortium risk classification. Among the 99 included patients, 41 initiated first-line therapy with VEGF-TT, 36 with IO + IO, and 22 with IO + VEGF-TT. The objective response rates were 17.5% for VEGF-TT, 38.9% for IO + IO, and 61.9% for IO + VEGF-TT. Notably, the IO + VEGF-TT group showed the greatest shrinkage of target kidney lesions (p = 0.0042). In multivariate analyses, bone metastasis (hazard ratio (HR) = 1.812, 95% confidence interval (CI) 1.017-3.228, p = 0.0436) and the first-line regimen (VEGF-TT vs IO + VEGF-TT: HR = 0.129, 95% CI 0.045-0.369, p = 0.0002) were independent prognostic factors for progression-free survival. The first-line regimen (VEGF-TT vs IO + VEGF-TT: HR = 0.303, 95% CI 0.104-0.879, p = 0.0279) independently affected overall survival. CONCLUSION: IO combination therapy, especially IO + VEGF-TT, has demonstrated a higher anti-tumor response in patients with advanced RCC without nephrectomy and may also be highly effective against primary renal tumors. Therefore, further studies are needed to improve patient survival and validate efficacy of IO combination therapy.