Background: Isolated limb hyperthermic-antiblastic perfusion (ILP) was the most effective local treatment for advanced in-transit melanoma, but the advent of modern effective immunotherapy (IT) such as immune checkpoint inhibitors has changed the treatment landscape. Methods: This study evaluated the role of the association between ILP and IT in the treatment of locally advanced unresectable melanoma, in particularly in relation to modern systemic therapies. We analyzed 187 consecutive patients who were treated with ILP (melphalan or melphalan associated with TNF-alpha) for advanced melanoma at the Veneto Institute of Oncology of Padua (Italy) and the Padua University Hospital (Italy) between June 1989 and September 2021. Overall survival (OS), disease specific survival (DSS), local disease-free survival (local DFS) and distant disease-free survival (distant DFS) were evaluated. Local toxicity was classified according to the Wieberdink scale and surgical complications according to the Clavien-Dindo classification. Response to locoregional therapy was evaluated during follow-up according to RECIST 1.1 criteria (Response Evaluation Criteria in Solid Tumor). Results: 99 patients were treated with ILP and 88 with IT+ILP. Overall response rate was 67% in both groups. At 36 months, OS was 43% in ILP group and 61% in ILP+IT group (p=0.02); DSS was 43% in ILP group and 64% in ILP+IT group (p=0.02); local DFS was 37% in ILP group and 53% in ILP+IT group (p=0.04); distant DFS was 33% in ILP group and 35% in ILP+IT group (p=0.40). Adjusting for age and lymph node involvement, receiving ILP+IT was associated with improved OS (p=0.01) and DSS (p=0.007) but not local DFS (p=0.13) and distant DFS (p=0.21). Conclusions: Our findings confirm the synergy between ILP and IT. ILP remains a valuable loco-regional treatment option in the era of effective systemic treatments. Further studies are needed to establish the optimal combination of loco-regional and systemic treatments, and address the best timing of this combination to obtain the highest local response rate.