Background: Ipilimumab (IPI) improves overall survival (OS) in patients (pts) with metastatic melanoma (MM), but the benefit in pts who progress on high dose IL-2 (HD IL-2) remains unknown. The primary endpoint was to determine if response to prior HD IL-2 would predict clinical benefit to IPI. The secondary endpoint was to determine if pts who progress on HD IL-2 receive clinical benefit from IPI versus other systemic therapies (OST). Methods: We reviewed the records of pts with MM who received systemic therapy after progressing on HD IL-2 at M. D. Anderson Cancer Center or Beth-Israel Deaconess Medical Center from 2004-2009. Pts in the IPI group received IPI at any point after progressing on HD IL-2 and OS was determined from the first dose of IPI. Pts in the OST group received non-IPI containing regimens and OS was calculated from first dose of OST. Pts were also grouped by their best response to HD IL-2: complete or partial response or stable disease (CR/PR/SD) versus progressive disease (PD). OS was determined by Kaplan-Meier analysis; groups were compared using the log-rank test. Results: Of the 208 pts treated with HD IL-2, 44 (21%) remain alive without systemic therapy, and 123 pts (62%) received systemic therapy after progression. Of the 123 pts who received systemic therapy, 47 (38%) received IPI and 76 (37%) received OST. In all pts treated with systemic therapy after HD IL-2, OS trended towards improvement in the CR/PR/SD versus PD subsets (2.4 vs 1.0 years, p=0.07). In the IPI group, pts with a CR/PR/SD to HD IL-2 did not have improved OS compared to pts with PD (1.2 vs 1.1 years, p=0.41). In the OST group, pts with a CR/PR/SD to HD IL-2 trended toward increased OS compared to pts with PD (2.4 vs 0.8 years, p=0.09). There was no difference in OS in all pts who received IPI or OST or in the CR/PR/SD or PD subsets. Conclusions: Prior response to HD IL-2 does not predict clinical benefit to IPI. There is no difference is OS in pts who progress on HD IL-2 and then receive either IPI or OST.