The anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) monoclonal antibody ipilimumab was the first in-class immune-checkpoint inhibitor (ICI) approved for the treatment of melanoma patients. Initially approved for metastatic cutaneous melanoma, treatment with ipilimumab subsequently demonstrated to significantly improve recurrence free survival (RFS) in fully resected, high-risk, stage III melanoma patients. Therapeutic use of ipilimumab has also allowed the initial identification and characterization of unconventional clinical and radiological patterns of response (ie, tumor flare, pseudo-progression) that may occur during ICI therapy, unlike chemotherapy or targeted therapy. As a result, the standard Response Evaluation Criteria In Solid Tumors (RECIST) and the World Health Organization (WHO) criteria conventionally utilized to assess responses to chemo/targeted therapy have been initially replaced by the immune-related (ir) Response Criteria (irRC) and then by the irRECIST, that encompass all patterns of response typical of ICI therapy, being key for the optimal comprehensive management of treated patients. Here, we report a paradigmatic clinical case of a long-term survival in a stage III melanoma patient, experiencing tumor flares during adjuvant treatment with ipilimumab, and an untreated disease relapse several years after ending therapy.