4514 Background: The role of immunotherapy combinations in mRCC with IMDC favorable risk is controversial. A very favorable subgroup of favorable risk patients (primary diagnosis to systemic therapy ≥3yr, Karnofsky Performance Status 90 or 100% and absence of brain, liver, or bone metastasis) has been described by Schmidt A. et al., which require characterization in the immuno-oncology combination era. Methods: Using the IMDC, we selected mRCC patients with IMDC favorable risk who started systemic therapy during 2016-2023 and examined the favorable risk group and the subset of very favorable risk patients. First line systemic therapy was divided into 3 groups: Ipilimumab + Nivolumab (IPI/NIVO), combination of anti PD1/PDL1 and VEGF (IO-VEGF) (Pembrolizumab and Axitinib or Lenvatinib, Avelumab and Axitinib, or Nivolumab and Cabozantinib), and Vascular endothelial growth factor (VEGF) inhibitors (Pazopanib or Sunitinib). The primary outcomes were 2-year overall survival (2y OS) in the favorable and very favorable risk population. Secondary outcomes included Response Rate (RR), treatment duration (TD) and time to next treatment (TTNT). We used unadjusted survival rates at 2 years, with Cox regression model with TKI mono as reference. Results: 611 favorable risk patients were eligible for analysis, of which 165 (26.9%) had very favorable risk disease. Median age at diagnosis was 62 years, 73.8% were male, 87.1% had clear cell histology, 5% had sarcomatoid features, and 97,2% had a prior nephrectomy. With a median follow up of 33 months, outcomes are summarized in the table. Conclusions: No significant difference in survival between different treatment regimens in the favorable risk population was detected yet. In the very favorable risk population, there was a statistically significant decrease in 2 year overall survival with IPI-NIVO (HR 3.19) which, if validated, could underline the necessity of targeting the VEGF pathway in this population. Further prospective trials and longer follow-up are required to confirm these findings. [Table: see text]