Background: Over the past decade opportunities for surgical treatment in metastatic melanoma patients have re-emerged due to the development of novel systemic therapies. However, selecting patients who will benefit from surgery after systemic therapy is still difficult. The aim of this study is to present data on outcomes of surgery in patients with unresectable stage III and IV melanoma, who have previously been treated with immune checkpoint inhibitors (ICI) or targeted therapy, to provide insight in which patients may benefit from surgery. Methods: Data was extracted from the prospectively collected, nationwide, Dutch Melanoma Treatment Registry (DMTR) onunresectable stage IIIC or advanced/metastatic stage IV melanomapatients who obtained disease control with systemic therapy and underwent subsequent surgery. Disease control was defined as a complete response (CR), partial response (PR) or stable disease (SD). After disease control was achieved with systemic therapy, progressive disease (PD) was allowed as a most recent status of disease prior to surgery, to avoid excluding patients with oligoprogression. Major exclusion criteria were non-cutaneous melanoma and brain metastases. Results: Of 3959 patients in the DMTR database, 154 patients met our inclusion criteria. Of these patients, 79 (51%) were treated with ICI, 61 (40%) with targeted therapy and 9.1% with study or other treatments before surgery. The best response to systemic therapy was a CR in 5.2%, PR in 46.1% and SD in 44.2% of patients. At a median follow-up of 10.0 months (IQR 4-22) after surgery, the median overall survival (OS) had not been reached in our cohort and median progression free survival (PFS) was 9.0 months (95% CI 6.3-11.7). A multivariate cox regression analysis showed that when surgery led to CR or PR, the PFS and OS were better than if surgery led to SD or PD (p < 001). Also, ICI seemed to be more favorable than targeted therapy in both PFS (median of 15 versus 7 months) and OS (median not reached versus 32 months) (p = 0.026 and p = 0.003). Conclusions: We conclude that selected unresectable stage IIIC or stage IV melanoma patients might benefit from surgery after achieving disease control with systemic therapy. Expected residual tumor after surgery could be an important selection criterion. Especially patients undergoing surgery after initial tumor response on ICI have a chance of long-term survival.