Background: The efficacy of ICI rechallenge for progressive/recurrent disease of advanced melanoma patients (pts) after a first course of ICI interrupted for disease control has not been systematically described. Methods: A retrospective observational multicenter national real-life study evaluated the efficacy and tolerance of ICI rechallenge (anti-PD1, anti-CTLA-4, or combination therapy) in melanoma pts who progressed after disease control with an ICI subsequently interrupted. Primary objective was to evaluate tumor response using RECIST version 1.1. Secondary objectives were the factors associated with tumor response, progression-free survival (PFS), overall survival (OS) and the tolerance of the rechallenge. Results: 85 pts from 12 French different centers rechallenged with an ICI between July 2014 and June 2021 were included. Median (IQR) age of pts was 72.00 (30–89) years. Most pts were male (n = 47, 55%) with an AJCC stage IV melanoma (n = 75, 88%). BRAFV600-mutant melanoma and elevated LDH were reported in 19 pts (22%). Pts were rechallenged with anti-PD1 (Pembrolizumab (n = 44, 52%), Nivolumab (n = 35, 41%)), anti-CTLA-4 (Ipilimumab (n = 2, 2%)) or the combination therapy (Ipilimumab + Nivolumab (n = 4, 5%)). Median follow-up after rechallenge was 13 months (1.1-76.2). All pts included had had disease control with the first course of ICI including complete response (CR) in 47 pts (55%), partial response (PR) in 28 pts (33%) and stable disease (SD) in 10 pts (12%). Adverse events (AEs) of the first course of ICI had occurred in 51% pts including grade 3-4 AEs (22%). Median time between ICI interruption and ICI rechallenge was 9,3 months (1.2-63,9). The response rates of ICI rechallenge (2^nd course of ICI) were CR in 30 pts (35%), PR in 17 pts (20%) and SD in 17 pts (20%). Progression occurred in 21 pts (25%). The use of steroids for brain metastases was the only factor associated with a higher recurrence rate in multivariate analysis (p = 0,002) and tends to be associated with lower outcomes. There was no correlation between best overall response to the first course of ICI and response to ICI rechallenge. Median duration of response, PFS and OS after ICI rechallenge were not reached. At last follow-up, 23 pts have died. 28 AEs of ICI rechallenge occurred in 23 pts (27%) with a median time of 3 (0.4-36.2) months, including grade 1-2 and grade 3-4 AEs in 13 (15%) and 9 (11%) pts respectively. Conclusions: ICI rechallenge for progressive/recurrent disease was associated with high objective response rate (CR+PR = 55%) and disease control rate (CR+PR+SD = 75%) in melanoma pts with a previous disease control induced by ICI. Thus, ICI rechallenge should be considered as an attractive therapeutic option for melanoma pts with progressive/recurrent disease after ICI interruption.