OBJECTIVES:  Glioblastoma (GBM) is the most common form of primary brain cancer. Prognosis is poor, with survival beyond 2 years being rare, and the economic burden being high. The objective of this study was to evaluate total cost of care (TCC) in patients treated for GBM. METHODS:  A retrospective GBM cohort study was conducted using US commercial and Medicare administrative healthcare claims data from Truven Health MarketScan®. Eligible patients were ≥18 years, had a malignant brain cancer diagnosis between 1/2010 and 9/2015, had brain-related surgery 90 days within diagnosis, received temozolomide (TMZ), radiation, or both within 90 days of diagnosis. TCC was calculated over 6- and 12- month periods following initiation of first-line (1L) or second-line (2L) treatment. RESULTS:  3,696 eligible patients with GBM were identified as receiving 1L with an average follow-up of 466 days. The majority 2,695/3,696 (73%) were treated with TMZ + radiation in 1L. During the 6 months prior to GBM diagnosis, cumulative mean direct medical costs was $12,040, with 82% incurred in the 3 months leading up to diagnosis, primarily as a result of hospitalizations. During the 6- and 12-month periods following 1L treatment start, mean total per-patient costs were $173,200 and $332,477, respectively. These were heavily driven by radiation costs. From 2L treatment to 6 and 12 months, the mean total per patient cost was $152,154 and $303,481, respectively, mainly resulting from systemic cancer therapy. Of the 3,696 patients identified in 1L, 31% patients received 2L. Most common treatments in 2L included bevacizumab (BEV) monotherapy (39%) and BEV in combination with other agents (30%). CONCLUSIONS:  This large real-world evaluation of TCC in patients with GBM demonstrates an extensive cost burden across the treatment continuum. Novel interventions are needed to improve outcomes as well as reduce TCC by influencing outpatient and inpatient costs.