4554 Background: IPI NIVO is approved for 1L treatment of IMDC intermediate/poor risk mRCC based on the CHECKMATE 214 trial. Herein, we report the clinical effectiveness of 1L IPI NIVO and second line (2L) therapy in the real-world setting. Methods: Using the IMDC dataset, patients (pts) treated with 1L IPI NIVO were identified. The outcomes of interest were 1L and 2L overall response rate (ORR), treatment duration (TD), time to next treatment (TTNT), and overall survival (OS). Results: 706 pts were included: 9% (57/614), 58% (354/614), and 33% (203/614) were IMDC favorable (fav), intermediate (int), and poor risk, respectively. Median age was 61 years. The majority of pts were males (71%), had clear cell histology (85%), and underwent nephrectomy (61%). 36%, 19%, and 8% of patients had bone, liver, and brain metastases, respectively. The 12-month OS for pts with IMDC fav, int, and poor risk disease was 92%, 79%, and 56%, respectively (p<0.01). The corresponding estimates for 24 months were 80%, 69%, and 38% (p<0.01). Pts who responded (39%) were more likely to have better IMDC risk category (p=0.02), received nephrectomy (p=0.04), normal neutrophil count (p<0.01), and clear cell histology (p=0.01). Pts with progressive disease as best response (27%) were more likely to have not received nephrectomy (p<0.01), worse IMDC risk category (p=0.02), bone metastases (p=0.01), liver metastases (p=0.04), and non-clear cell histology (p=0.01). Of the 66% (466/706) of pts who discontinued 1L IPI NIVO, 51% (236/466) received 2L therapy: sunitinib (40%), cabozantinib (25%), pazopanib (18%), axitinib (8%), and others (9%). The ORR, median TD, and median OS for those who received either sunitinib, cabozantinib, pazopanib or axitinib was 16%, 4.5 months (mo) (95% CI 3.7-5.6), and 14.5 mo (95% CI 10.9-25.9), respectively. 33% (129/386) of pts discontinued IPI NIVO due to irAEs. Conclusions: Our study benchmarks the real-world experience of 1L IPI NIVO in mRCC. IMDC criteria is prognostic for clinical outcome. Tyrosine kinase inhibitors have clinical activity post IPI NIVO.[Table: see text]