OBJECTIVES: Malignant metastatic melanoma (MMM), the most serious form of skin cancer, currently accounts for 79% of all skin cancer deaths, and is becoming increasingly common. MMM patients have limited treatment options and low survival rates. The five-year survival rate for patients with regional melanoma is 63.8%, compared to 16.0% for patients with metastatic melanoma. Despite the importance of this cancer, data on its economic burden are limited. METHODS: A prevalence-based model was developed to estimate the aggregate annual cost burden attributable to MMM from a societal perspective, including costs of medical treatment and lost productivity in the US. Key relationships represented in the model include the annual numbers of patients treated for MMM by age group; utilization of cancer-specific treatments; unit costs of these treatments; work days missed by these patients; and wage rates. Data sources included the linked Surveillance, Epidemiology and End Results (SEER)–Medicare database, the Bureau of Labor Statistics, and published literature. RESULTS: The annual prevalence of MMM in the US was estimated to be 5778 cases. The associated annual cost burden was estimated at approximately $202 million ($34,991 per patient) in 2005. Healthcare costs and lost productivity accounted for 87.1% ($176 million) and 12.9% ($26 million) of the total burden, respectively. The principal cost driver was cancer-related hospitalization (accounting for 31.4% of total healthcare costs) for procedures including lymphadenectomy, radiofrequency ablation, chemotherapy, and arterial embolization. SNF services, hospice care, physician services and outpatient hospital services accounted for 5.8%, 5.9%, 11.6% and 8.0% of healthcare costs, respectively. Sensitivity analyses varying assumptions regarding healthcare utilization and wage rates resulted in a range in the estimated annual burden from $207 to $216 million. CONCLUSION: The economic burden of MMM in the US is substantial. New therapies for MMM have the potential to yield considerable economic benefits to society.