Melanoma of unknown primary (MUP) may have a different biology to melanoma of known primary, but clinical trials of novel therapies (e.g., immune checkpoint or BRAF/MEK inhibitors) have not reported the outcomes in this population. We therefore evaluated the overall survival (OS) among patients with MUP in the era of novel therapy. Data for stage III or IV MUP were extracted from a nationwide database for the period 2003-2016, with classification based on the eighth edition of the American Joint Committee on Cancer criteria. The population was divided into pre- (2003-2010) and post- (2011-2016) novel therapy eras. Also, OS in the post-novel era was compared between patients with stage IV MUP by whether they received novel therapy. In total, 2028 of 65,110 patients (3.1%) were diagnosed with MUP. Metastatic sites were known in 1919 of 2028 patients, and most had stage IV disease (53.8%). For patients with stage III MUP, the 5-year OS rates were 48.5% and 50.2% in the pre- and post-novel eras, respectively (p = 0.948). For those with stage IV MUP, the median OS durations were unchanged in the pre-novel era and post-novel era when novel therapy was not used (both 4 months); however, OS improved to 11 months when novel therapy was used in the post-novel era (p < 0.001). In conclusion, more than half of the patients with MUP are diagnosed with stage IV and the introduction of novel therapy appears to have significantly improved the OS of these patients. © 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.