Background: Current systemic therapies of metastatic melanoma (MM) include immunotherapy, target therapy (if BRAF mutated), high-dose IL-2, and chemotherapy, all of which are associated with different toxicity and adverse events (AEs). A comprehensive understanding of the costs of AEs will enable more accurate comparisons among the treatments and better management of costs. Methods: Two retrospective cohort studies were independently conducted using IMS PharMetrics Plus databases and MarketScan commercial and Medicare supplemental databases. Patients included those aged ≥ 18 years who had ≥ 1 metastatic melanoma diagnosis and ≥ 1 claim for any systemic therapies from July 1, 2004 to June 30, 2015. AEs were identified based on ICD-9-CM diagnosis/procedure codes. Incremental cost per AE was determined by comparing the 30-day expenditures between patients with the AE event and patients without the event using a generalized linear model. Propensity score with inverse probability of treatment weighted method was used to adjust for baseline demographic and clinical differences. Results: 1,654 patients from PharMetrics were included. Mean age was 61.2 years (SD ± 11.4); mean baseline Charlson comorbidity index was 8.0 (SD ± 2.3); 59% were male. 1,329 patients included from MarketScan had similar characteristics. The adjusted 30-day incremental costs by AE category in 2015 US$ are summarized below in the table. Conclusions: Incremental AE costs associated with systemic therapies of mm are substantial.