Methionine is an essential amino acid critical for cell growth and survival. Preclinical evidence suggests a methionine restricted diet (MRD) sensitizes cancer to radiation therapy (RT), without significant adverse effects. However, this has never been evaluated in humans. The purpose of this pilot study was to evaluate the safety and feasibility of concurrent MRD with standard-of-care definitive RT in adults with any non-skin cancer malignancy. The MRD extended from 2 wk before RT initiation, through 2 wk beyond RT completion. The primary endpoint of safety was assessed as rate of grade 3 or higher acute and late toxicities. Feasibility was assessed with quantitative plasma amino acid panel every 2 wk during the MRD (target plasma methionine 13 μM). Nine patients were accrued over a two-year period, with five able to complete the treatment course. The trial was closed due to slow accrual and subjects' difficulty maintaining the diet. No grade 3 or higher adverse events were observed. Subjects' average methionine level was 18.8 μM during treatment, with average nadir 16.8 μM. These findings suggest the safety of concurrent MRD with RT, with toxicities comparable to those expected with RT alone. However, the diet was challenging, and unacceptable to most patients.