Purpose: It is currently unknown whether increasing radiation therapy (RT) volume has a negative impact on the health-related quality of life (HRQoL) of patients with low-grade glioma in the short term. The aim was to examine whether the size of the target volume is independently associated with HRQoL. Methods and Materials: We included patients who were treated with radiation therapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 study and who completed baseline HRQoL assessment. HRQoL was measured at baseline and every 3 months thereafter until progression, using the European Organisation for Research and Treatment of Cancer quality of life and brain cancer module questionnaires (QLQ-C30 and QLQ-BN20). We investigated whether there were associations between radiation volumes and (changes in) 4 preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue). Also, we determined if radiation volumes were independently associated with a change in HRQoL over time. Results: We included 195 of 240 patients (81.3%) randomized to radiation therapy in this analysis. The brain volume receiving radiation therapy was not associated with (changes in) HRQoL during the first 24 months after radiation therapy. Over time, radiation volumes were also not independently associated with HRQoL. Notably, the occurrence of tumor progression was found to be associated with worse functioning and more fatigue. Conclusions: The brain target volume receiving focal radiation therapy in fractions of 1.8 Gy to a total of 50.4 Gy did not appear to be independently associated with HRQoL in high-risk patients with low-grade glioma in the short term, as opposed to tumor progression. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated.