OBJECTIVES: To assess the cost of HER2-positive (HER2+) metastatic breast cancer (mBC) for patients initiating an oral anticancer treatment (OAT) from the perspective of the French National Health Insurance (NHI). METHODS: A prospective observational multicenter study was conducted among 284 HER2+ mBC patients treated by 68 oncologists initiating a treatment containing an OAT between March 2011 and February 2012. Costs data were available for 199 patients. Clinical characteristics, treatment patterns, quality-of-life, adherence and healthcare resources data were collected. Healthcare resource use data on hospitalization, medical consultation, drug and radiation-therapy were reported by oncologists at treatment initiation and after each 3-month period during a 9 months maximum period. Cost estimations were based on unit costs from national databases (French Diagnosis Related Group cost database and NHI database for drug unit cost). RESULTS: A total of 109 patients (55%) received an OAT only and 90 (45%) received oral and intravenous (IV) drugs. Thirty patients (15%) were treated with radiation therapy and 43 patients (22%) with hormonal-therapy in addition to chemotherapy. The overall average cost of management per patient was 28,482€ ± 14,914 for all patients, 19,412€ ± 9,462 for patients with an OAT only and 39,467€ ± 12,770 for patients with oral and IV drugs. Drug costs were 27,669 € ± 14,976 and they represented 97% of the total hospital cost of management (hospitalizations, consultations and drugs). CONCLUSIONS: This prospective observational study conducted among HER2+ mBC patients shows that the route of drug administration has an impact on treatment costs. Nevertheless, the study design does not allow concluding that OAT were associated with lower costs and cost savings. These finding however warrants further exploration within the context of micro-costing studies from the hospital and community perspective in order to better understand the health care resources used that are required to manage patients treated with OAT.