Background: Approved treatments for metastatic melanoma (MM) and metastatic renal cell carcinoma (mRCC) include targeted agents, high dose interleukin-2 (HD IL-2) and checkpoint inhibitors (CI). A subset of responders to HD-IL2 can achieve long term durable remissions (7-10%). Recently, data suggests that durable remissions are possible with CI. Thus, despite increased toxicity, first-line immunotherapy with HD-IL2 is a reasonable consideration in carefully selected patients with clear cell mRCC and MM followed by CI upon relapse. Our study explores the utility and safety of CI subsequent to HD-IL2 in patients (pts) in this population.Methods: We conducted a single institution retrospective analysis of pts with MM or mRCC who received HD-IL2 and subsequent CI from 2008-2017. Pts treated with prior targeted therapy were included. Statistical analysis was performed using Fischer's exact tests, log-rank test for KM analysis and non-parametric Wilcoxon Rank Sum tests to compare the groups. Results: We identified 34 unique pts (19 MM, 15 mRCC) from our pre-specified cohort. Pts were male (73%), Caucasian (88%), and median age=53. mRCC pts received more cancer related treatments than MM prior to CIs after HD-IL2 was given (2 vs. 1, p=0.002), had more total CI cycles administered (12 vs. 7, p=0.10) but less IL-2 doses than MM pts (20 vs. 24, p=0.26). mRCC pts tended to record higher HD-IL2 toxicity grade compared to MM pts (exact =0.04). 26% (9/34) of pts experienced a grade 2 or higher CI toxicity. Pts had higher HD IL-2 toxicities than CI toxicities during therapy but these two measures were not significantly correlated (r=0.07, p=0.73); furthermore, there was no survival difference between pts with reported grade 2 or higher CI toxicity compared to pts without any CI toxicity (p=0.14). Conclusions: Our study suggests that CI therapy after HD-IL2 is feasible and not associated with more frequent toxicity or less clinical efficacy in pts with MM or mRCC.