Background: Several studies have compared the survival rate of melanoma of unknown primary (MUP) patients with patients with a known primary melanoma (MKP). Some studies found improved survival in MUP patients, whereas others found similar or poorer outcomes. The aim of this study was to evaluate if there was a difference in survival between patients with MUP and patients with a MKP with stage III and IV disease. Methods: A retrospective study was conducted of 48 MUP patients and 502 MKP patients diagnosed with American Joint Committee on Cancer (AJCC) stage III and 92 MUP patients and 218 MKP patients diagnosed with AJCC stage IV melanoma at Aarhus University Hospital and Odense University Hospital, Denmark, between 2003 and 2013. Results: Multivariate analysis of data identified no significant survival differences between MUP and MKP patients with stage III (hazard ratio [HR] = 0.84; P = 0.46) and stage IV (hazard ratio [HR] = 1.03; P = 0.84) disease. Conclusions: This study included patients from two major university hospitals in Denmark and showed no difference in overall survival between MUP and MKP patients with stage III or IV disease. Level of Evidence: Level IV, risk/prognostic study.