OBJECTIVES: The prognosis of melanoma patients with brain metastases is poor, with median overall survival of approximately 4-5 months. This is the first study aiming at quantifying medical resources utilization and direct healthcare costs associated with brain metastases among metastatic melanoma patients in the U.S. METHODS: A retrospective pre-post design was implemented using data from the Truven MarketScan claims database (2000Q1-2011Q3). Patients with ≥1 diagnosis of melanoma (ICD-9-CM: 172-173, 198.2), ≥1 diagnosis of brain metastases (ICD-9-CM: 198.3), and ≥18 years as of the first observed brain metastases diagnosis (index date) were identified. The pre-period was defined as the 6 months prior to the index date and post-period as the period following the index date up to the earliest of 12 months, recorded death, or loss to follow up. All-cause and brain metastasis-related medical resources and healthcare costs were compared on a per patient per month (PPPM) basis between the pre- and post-periods. RESULTS: The study population consisted of 6076 patients; mean (SD) age was 63.4 (13.4) years and 57.6% males. Significant differences were observed between the post- and pre-period in mean all-cause PPPM hospitalizations (0.21 vs. 0.08), emergency department visits (0.12 vs. 0.08), and outpatient visits (4.48 vs. 3.74) (p<.0001 for all). Similar results were found for brain metastasis-related hospitalizations (0.15 vs. 0.04), emergency department visits (0.02 vs. 0.01), and outpatient visits (2.00 vs. 1.17) (p<.0001 for all). Significant post- vs. pre-period differences were also observed in the PPPM all-cause healthcare costs (total: $14,489 vs. $7,277; inpatient: $6,330 vs. $1,900; outpatient: $6,609 vs. $4,449; p<.0001 for all) and brain metastasis-related costs (total: $6,542 vs. $1,933; inpatient: $2,976 vs. $472; outpatient: $3,451 vs. $1,413; p<.0001 for all).  CONCLUSIONS: The economic burden associated with brain metastases in melanoma is significant and underscores the need for newer therapies improving outcomes among these patients.