BACKGROUND In this prospective study, the authors evaluated potential treatment toxicity and progression‐free survival in patients with low‐grade glioma who received treatment with proton radiation therapy. METHODS Twenty patients with World Health Organization grade 2 glioma who were eligible for radiation therapy were enrolled in a prospective, single‐arm trial of proton therapy. The patients received proton therapy at a dose of 54 Gy (relative biological effectiveness) in 30 fractions. Comprehensive baseline and regular post‐treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS All 20 patients (median age, 37.5 years) tolerated treatment without difficulty. The median follow‐up after proton therapy was 5.1 years. At baseline, intellectual functioning was within the normal range for the group and remained stable over time. Visuospatial ability, attention/working memory, and executive functioning also were within normal limits; however, baseline neurocognitive impairments were observed in language, memory, and processing speed in 8 patients. There was no overall decline in cognitive functioning over time. New endocrine dysfunction was detected in 6 patients, and all but 1 had received direct irradiation of the hypothalamic‐pituitary axis. QOL assessment revealed no changes over time. The progression‐free survival rate at 3 years was 85%, but it dropped to 40% at 5 years. CONCLUSIONS Patients with low‐grade glioma tolerate proton therapy well, and a subset develops neuroendocrine deficiencies. There is no evidence for overall decline in cognitive function or QOL. Cancer 2015;121:1712–1719 . © 2015 American Cancer Society .