Background: The survival of patients with melanoma of unknown primary (MUP) is proposed to be more favourable than that for melanoma of known primary (MKP). This may be due to an enhanced initial immune response in patients with MUP, which could also affect the efficacy of immunotherapy in advanced disease. Objectives: The present study compared therapeutic outcome and survival in Stage III and IV MUP and MKP. Results: Medical records of 67 MUP and 536 MKP patients were reviewed. Median overall survival (OS) in Stage III patients was 77 months versus 54 months in patients with MUP and MKP, respectively (p = 0.11). Median OS was prolonged in MUP patients receiving adjuvant first-line ipilimumab (p = 0.14). In contrast, OS tended to be more favourable in patients with MKP after palliative first-line ipilimumab treatment (p = 0.16). Yet, no statistically significant differences in OS were detected between the groups. Moreover, survival after anti-PD-1-antibody treatment was similar in patients with MUP and MKP. Conclusion: Overall, we observed similar survival outcomes after immunotherapy in patients with MUP and MKP. These findings provide no evidence of difference in responsiveness to immunotherapy between patients with MUP and MKP.