Background: The optimal treatment algorithm for noncutaneous melanomas must yet be established. Objective: To compare systemic treatment-relevant mutational status, metastatic pattern and response to systemic treatment in noncutaneous melanoma. Methods: Retrospective single-center study analyzing 64 noncutaneous melanoma patients treated between January 2006 and September 2013. Results: c-KIT mutations were found exclusively in vulvovaginal melanoma (4/7). Overall status for NRAS and BRAF mutations was low (1/7 and 0/21 detected mutations, respectively). Seven out of 7 vulvovaginal and 6/13 sinonasal melanomas first metastasized to lymph nodes, whereas 18/22 ocular melanomas first metastasized to the liver. Response to systemic treatment in vulvovaginal melanomas was best for imatinib with a disease control rate of 3/3 and overall for ipilimumab with a disease control rate of 3/10. Sorafenib was associated with adverse drug reactions (6/13) and poor results. Conclusion: Noncutaneous melanomas show few tumor-signaling pathway mutations and distinct metastasization patterns. Immunotherapy induces response rates in mucosal melanoma similar to those in cutaneous melanoma.