Background: Mucosal melanoma (MM) is a molecular and clinical subset of melanoma distinct from cutaneous melanoma (CM). The activity of systemic therapy (tx) in MM has not been rigorously evaluated. We performed a retrospective, single center analysis of MM patients (pts) treated with systemic tx. Methods: Using institutional databases, we identified pts with MM who were 1) treated at MSKCC between 1998-2012; 2) developed unresectable or metastatic disease (dz); 3) received ≥1 non-adjuvant systemic tx; 4) had scans available for blinded central radiology review using RECIST 1.1. Pt demographics and clinical outcomes were extracted. Results: 61 pts met inclusion criteria. Median age at diagnosis 64 years (range, 35-84); 71% female; primary site: 28 anorectal, 19 vulvovaginal, 13 head/neck, 1 gallbladder. Mutation (mut) status: 8/35 KIT mut (7 exon 11; 1 exon 13); 3/33 BRAF mut (all non V600mut); 3/33 NRAS mut. At time of 1^st tx, 55 had metastatic dz (10 M1a, 6 M1b, 39 M1c) and 6 had locally advanced dz. Pts received 106 1st or 2nd-line systemic tx: 81 cytotoxic (24 single-agent alkylators [eg. TMZ, DTIC]; 47 alkylator-based combinations [eg. Cisplatin/Vinblastine/TMZ]; 10 other combinations); 11 immunotherapy [7 ipilimumab, 2 high-dose IL-2, 2 other]; 9 targeted [8 KIT inhibitors, 1 BRAF inhibitor]; 4 biochemotherapy; 1 other investigational tx. Overall response rate (RR) rate to 1^st and 2^nd-line tx was 16% and 13%, respectively, with no complete responses. 24-week (wk) dz control rate with 1^st and 2^nd-line tx was 20%, and 9%, respectively. RR in either 1^st or 2^nd-line to single-agent and combination alkylator tx was 8% (2/24), and 15% (7/47), respectively (p=0.71). RR to targeted tx and immunotherapy was 33% (3/9), and 9% (1/11), respectively. Median time to treatment failure (earlier of date of progression or change in therapy) was 11 wks (95% confidence interval [CI] 8-14 wks) for both 1^st and 2^nd line tx. Median overall survival (OS) from initiation of 1^st-line tx was 11 mo (95% CI 8-13 mo). Conclusions: The efficacy of systemic tx in MM is modest and appears similar to that seen in CM. Clinical outcomes for this pt population are poor. Further investigation into the biology and treatment of MM is needed.