Background: IL-2 can be curative in a small subset of ccRCC patients (pts). Recent data suggest that ICIs may lead to long lasting responses, and ICI therapy following progression on IL-2 seems reasonable. However, data regarding the safety and efficacy of ICI following IL-2 is limited. Methods: ccRCC pts treated with ICI after first line were identified at UT Southwestern Medical Center from 2014 – 2018 and assessed by comparison to IL-2 naïve pts at the time of ICI initiation. Outcomes included objective response rates (ORR) determined by RECIST v1.1, time to next treatment (TNT) and overall survival (OS). Immune-related adverse events (irAEs) were graded per CTCAE v4.0. Comparisons were performed using Pearson Chi-square, independent t-tests, and Fischer’s exact tests as appropriate. The log-rank test was utilized for Kaplan-Meier survival analyses. Results: We identified 127 ccRCC pts treated with ICI after first line, 17.3% (22) who had received prior IL-2 and 83.7% (105) who were IL-2 naïve. Pts in the IL-2 group were younger (mean age, 56 vs. 63 years; p=0.003), and more heavily pretreated (median 2 prior lines vs. 1; p <0.0001). The distribution by IMDC criteria was similar with 86.4% (19) and 76.4% (81) in intermediate/ poor group in IL-2 vs. IL-2 naïve groups, respectively (p = 0.431). The ORR was 9.1% (2/22) vs. 21.2% (22/104) in the IL-2 vs. IL-2 naïve groups, respectively (p=0.244). The median TNT was 7.5 (95% CI: 1.8 to 13.2) vs. 9.2 (95% CI: 6.0 – 12.4; p= 0.667) months in the IL-2 vs. IL-2 naïve groups, respectively. The median OS was 26.4 (95% CI: 17.3 – 35.5) vs. 29.8 (23.1 to 36.4) months in the IL-2 vs. IL-2 naïve group, respectively. 18.2% (4) vs. 21.9% (23) pts developed a grade 3/4 irAE in the IL-2 vs. IL-2 naïve group, respectively (p=0.698). Conclusions: Our study suggests that ICI therapy following treatment with high-dose IL-2 remains efficacious and is not associated with an increased risk of irAEs.