Background: Over half of patients (pts) diagnosed with Renal Cell Carcinoma require systemic therapy for metastatic disease (mRCC). Approved first line treatment includes immunotherapy and targeted therapy (TT). TT is commonly used given its efficacy, favorable side effect profile, and convenience of oral administration. High dose IL-2 (HD-IL2) can induce durable long term remissions in a subset of pts. There is limited data on the efficacy of HD-IL2 after disease progression on TT. Methods: All pts treated with HD-IL2 for mRCC from 2008-2014 were reviewed. A focused analysis was performed on pts who received HD-IL2 after first-line TT. Three pts were excluded from analysis. Data regarding pt demographics, health status, disease related characteristics, prognostic factors, treatment history and toxicity were captured. Response to HD-IL2 was also classified using RECIST definition. Utilizing descriptive statistics, we examined response rates, toxicities, and outcomes in this subset of pts. Results: Eighteen pts received HD-IL2 after TT. Median age was 60 (range 48-72). Six pts had primary mRCC and 12 had recurrent mRCC. Twelve pts received HD-IL2 as a 2nd line of treatment. Six pts received HD-IL2 as a 3rd or higher line of treatment. Among pts treated with HD-IL2 as 2nd line, 8 pts (67%) had partial response and 1 (8%) had complete response; duration of response ranged from 5-20+ months and 3 pts remain in remission. All 6 pts treated as 3rd line or higher did not show objective response to HD-IL2. The 2nd line group received significantly more doses than pts treated as 3rd line or higher (mean doses, 37 vs. 18, p=0.01). Overall, adverse events were expected, with the exception of grade 4 cardiac toxicity in 2 pts who received HD-IL2 as 3rd line. Conclusions: The administration of HD-IL2 as 2nd line is tolerated without excess toxicity and can induce clinical response. In our sample, there was no response to HD-IL2 among pts who received two or more prior TT. More investigation is warranted to determine if 3rd line HD-IL2 is safe and retains clinical benefit.