OBJECTIVES: Information on the costs of managing adverse events (AEs) associated with currently-available treatment regimens in advanced melanoma is limited.  This study identifies treatment-related AEs associated with commonly-used regimens recommended in US guidelines, and estimates the costs of treating these AEs in the US. METHODS: Grade 3 and 4 AEs were identified by a comprehensive literature search of product labels and published English-language phase II/III advanced melanoma studies in PubMed, conference abstracts, and NCCN guidelines. In-depth interviews with 5 US melanoma clinicians were performed to obtain resource utilization and treatment setting information for managing each type of AE. Costs (2012$) were then estimated for each type of AE in outpatient and inpatient settings, using Medicare reimbursement rates for the outpatient setting, and Healthcare Utilization Project estimates for the inpatient setting. RESULTS: The most common grade 3 and 4 AEs associated with chemotherapy regimens included neutropenia, vomiting, and anemia. Cutaneous squamous cell carcinoma (CSCC)/keratoacanthoma, rash, and elevated liver enzymes were most common AEs associated with vemurafenib, while CSCC and pyrexia were most often associated with dabrafenib. The most common AEs associated with trametinib were hypertension and rash. Common ipilimumab AEs included immune-related diarrhea/colitis, dyspnea, anemia, and vomiting, and less frequent hypophysitis.  The highest cost per incident in the outpatient setting among these AEs was neutropenia ($2,039), followed by CSCC ($369), vomiting ($342), and dyspnea ($222). The highest costs per hospitalization were for CSCC ($18,906), followed by hypophysitis ($15,721) and febrile/afebrile neutropenia ($11,125). Other costly AEs in the inpatient setting include hypertension ($8,113), diarrhea ($6,881), dyspnea ($6,826), vomiting ($6,046), anemia ($6,014), and elevated liver enzymes ($5,942). All hospitalizations due to AEs were more than $4,000 per incident. CONCLUSIONS: The costs of managing treatment-related AEs in advanced melanoma are considerable, and there is need for effective treatments with improved toxicity profiles.