OBJECTIVES: To evaluate adherence to cancer therapies among patients with advanced melanoma and quantify the impact of drug adherence on healthcare costs. METHODS: Patients (≥18 years) with a diagnosis for stage III/IV melanoma who initiated cancer therapies were identified from the MarketScan Commercial and Medicare databases (1/1/2011-8/31/2015). Demographic and clinical characteristics were evaluated at baseline (12 months preindex). Medication adherence and persistence were examined during a variable length follow-up period for up to 24 months. Patients were grouped into 2 study cohorts: those with high adherence (medication possession ratio, MPR≥0.8) and those with low adherence (MPR<0.8) to the index cancer therapy. All-cause and melanoma-related costs were measured as per patient per month (PPPM, 2015 USD) at follow-up and compared among study cohorts. A multivariate generalized linear model was used to evaluate the impact of adherence status on healthcare costs, while controlling for key patient characteristics. RESULTS: In the overall study population (N=2,671), the mean[±SD] age of the patients was 60.9[±13.3] years, 63.6% were male, with a mean[±SD] Charlson comorbidity index score of 8.8[±2.0], and 85.5% had stage IV melanoma. 49.1% of the patients were on an immunotherapy and 94.7% of those patients recieved ipilimumab. The mean[±SD] MPR of patients decreased as the duration of follow-up increased, ranging from 0.75[±0.24] at 3 months to 0.44[±0.29] at 24 months of follow-up. Nearly three-fourths (72.4%) of the patients discontinued their index therapy within 3 months. After controlling for patient characteristics, those with high vs. low adherence had lower mean PPPM all-cause total cost ($41,830 vs. $51,991; p<0.001) and melanoma-related total cost ($37,549 vs. $48,263; p=0.006). CONCLUSIONS: A majority of patients with advanced melanoma have low adherence and discontinue therapy in ≤3 months. Patients with high adherence to cancer therapies have lower all-cause and melanoma-related total costs than patients with low adherence.