Using a large national claims database, this study investigates the differences in survival and healthcare costs of metastatic melanoma patients by the number of metastatic sites. An analysis was carried out using data obtained from January 2007 to March 2010. Patients included had at least two claims for metastatic disease at least 30 days apart, at least two claims for melanoma at least 30 days apart, or at least one claim for cancer-related treatment with a diagnosis of melanoma and evidence of anticancer systemic therapy. The index date was the first metastatic diagnosis date. Patients were characterized as having evidence of lymph node (LN) involvement only, 1–3 distant metastatic sites, or 4+ distant metastatic sites. Average per-patient per-month (PPPM) costs and mortality were examined. There were 431 metastatic melanoma patients: most were male (65%) with mean baseline Charlson’s comorbidity index of 3.52. The mean (SD) total unadjusted costs PPPM in the follow-up period were lower for patients with metastases to LN only ($6773 [$5521]) than for those who had 1–3 ($10 999 [$11 319]) or 4+ ($15 762 [$12 377]) distant metastases (P<0.001). When compared with patients with LN metastases only, patients having 1–3 [cost ratio (CR): 1.739, P<0.001] or 4+ (CR: 2.375, P<0.001) distant metastatic sites had higher all-cause healthcare costs. Among the entire study cohort, 42% died with a median survival time of 270 days. Mortality varied by cohort: 3% in LN only; 37% in 1–3 non-LN, and 64% in >3 non-LN (P<0.001). In conclusion, patients with metastatic melanoma with a greater number of metastatic sites have increased healthcare costs and significantly worse survival times.