Ipilimumab improves overall survival (OS) in patients with metastatic melanoma including those previously treated with high-dose interleukin-2 (HD IL-2). The primary objective of this study was to determine if clinical response or progression-free survival (PFS) to HD IL-2 could predict benefit to subsequent ipilimumab. The secondary objective was to further characterize the clinical benefit of ipilimumab in patients who have progressed on HD IL-2. We reviewed the records of all patients with metastatic melanoma who received HD IL-2 at MD Anderson Cancer Center or Beth Israel Deaconess Medical Center from 2003 to 2009 and further identified patients who also received ipilimumab after progressing on HD IL-2. OS to ipilimumab was calculated from the first dose of ipilimumab, determined by Kaplan-Meier analysis, and was compared in patients based on their prior clinical response and PFS to HD IL-2 using the log-rank test. Patients were grouped based on their prior response to HD IL-2 as follows: complete response and partial response, stable disease, and progressive disease. Patients were also grouped and compared by prior PFS to HD IL-2 in >60 days versus ≤60 days. A total of 208 patients with melanoma were treated with HD IL-2, 130 (63%) received additional systemic therapy after confirmed disease progression, and 48 (23%) received ipilimumab. The clinical benefit of ipilimumab was similar to previously published results (OS, 12.0 mo; PFS, 2.5 mo; response rate, 16.7%). Prior clinical response or PFS to HD IL-2 did not predict benefit to subsequent ipilimumab. Prospective trials of HD IL-2 followed by ipilimumab could potentially identify patients most likely to benefit from a sequential approach of HD IL-2 followed by ipilimumab.