Background: Presented with a dismal prognosis and limited treatment options, many glioblastoma (GBM) patients seek complementary interventions. Of particular interest is a high-fat / low-carbohydrate diet known as the ketogenic diet (KD). Preclinical models and results from early-phase trials suggest potential benefits with KD for patients with GBM receiving standard-of-care (SOC) treatment, but definitive evidence of clinical efficacy is still lacking. Methods: We are conducting a multicenter randomized controlled phase 2 clinical trial of KD vs standard dietary guidance (SD) for patients with newly diagnosed GBM. All patients will receive SOC chemoradiation. Patients with newly diagnosed GBM age ≥ 18 years with Karnofsky Performance Status ≥ 70 are eligible. Exclusion criteria include inability to wean steroids below 8 mg dexamethasone/day or equivalent, Body Mass Index < 21 kg/m², or food preferences incompatible with KD. Patients are randomized 1:1 to implement either KD (3:1 ratio between grams of fat to grams of carbohydrates + protein) or SD (based on guidelines from the American Cancer Society and American Institute of Cancer Research) for a study period of 18 weeks, starting the same time as chemoradiation. Post-randomization, all patients receive diet education, followed by in-person or virtual dietitian consultation every 2 weeks at minimum while on study. The primary objective is to assess overall survival for patients on the KD arm vs the SD arm. Secondary endpoints include assessments of progression-free survival, health-related quality-of-life (FACT-BR, FACIT-F), cognitive performance (HVLT-R, Trail-Making Test A/B), and physical activity (modified Godin leisure questionnaire, continuous activity monitoring (Fitbit)), as benefits in any of these domains would be impactful for patients. Patients randomized to the KD arm will be provided a fingerstick monitor (Keto-Mojo) to check blood ketone and glucose levels daily. Glucose and ketone levels are also periodically monitored for patients on the SD arm. Blood, tumor, and stool samples are being collected for high throughput profiling to assess the effects of KD on metabolic markers and immune response. While the primary analysis for this study is intent-to-treat, we will also perform secondary per protocol and as-treated analyses using food diaries plus glucose and ketone data. Target accrual is 170 patients over 5 years. Enrollment began in July 2023 and is ongoing. As of January 2024, the trial is open for enrollment at Cedars-Sinai Medical Center and will be opening at UCSF, Duke, Pacific Neuroscience Institute, and the Medical College of Wisconsin soon. Ten patients have been randomized so far. This trial is funded by NIH R01CA276919 and a grant from the Foundation for Metabolic Cancer Therapies and is registered as NCT05708352. Clinical trial information: NCT05708352.