Background: High-dose interleukin-2 (HD IL-2) and immune checkpoint inhibitors can provide survival benefit in patients with metastatic melanoma (mM). The clinical impact of using these therapies in sequence remains unknown. Herein, we report on the outcomes of sequencing ipilimumab and/or anti-PD-1/PD-L1 therapy after treatment with HD IL-2 using a national IL-2 patient registry, PROCLAIM^SM (www.proclaimregistry.com, NCT01415167). Methods: Patients were prospectively enrolled into the registry as of 2011 and must have received at least one dose of HD IL-2 for this analysis. Those that received immune checkpoint inhibitors prior to HD IL-2 were excluded. Statistics and survival analysis were performed on datasets as of December 2, 2015. Results: The mOS for all mm patients (n = 273) was 19.4 months, with a median follow-up of 23.1 months. Three groups were further analyzed according to treatment after HD IL-2; no immune checkpoint blockade following HD IL-2 (no ICB, n = 137), HD IL-2 followed by ipilimumab alone (IL-2 then IPI, n = 82), and HD IL-2 followed by anti-PD-1/PD-L1 inhibitors with or without ipilimumab (IL-2 then aPD-1±IPI, n = 54). This latter group, IL-2 then aPD-1±IPI, could have received ipilimumab before or after anti-PD-1/PD-L1. Patients with no ICB, IL-2 then IPI, and IL-2 then aPD-1±IPI achieved a mOS of 14.1, 15.8, and 28.2 months, respectively (P= .96 IL-2 then IPI vs. no ICB; P= .002 IL-2 then aPD-1±IPI vs. no ICB). The estimated 12-month survival rates were 56%, 64%, and 96%, respectively. No HD IL-2 treatment-related deaths were reported. Conclusions: There was no difference in mOS between patients treated with ipilimumab post HD IL-2 compared to patients with no ICB following HD IL-2. Patients treated with anti-PD-1/PDL-1±IPI showed increased mOS compared to those treated with HD IL-2 alone. These data further support the concept of investigating IL-2 therapy in combination or sequence with newly developed immune checkpoint inhibitors. Clinical trial information: NCT01415167