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The present study assessed the effect of prostate gland size on patient-assessed quality of life (QOL) after definitive treatment of prostate adenocarcinoma with proton beam therapy. A larger prostate size, despite receiving a greater radiation dose, did not affect QOL at 6 months, providing further support that neoadjuvant cytoreductive treatments are unnecessary.In the present study, we assessed the effect of prostate gland size on patient-assessed genitourinary and gastrointestinal (GI) quality of life (QOL) after definitive treatment of prostate adenocarcinoma with proton beam therapy.As a part of a prospective outcome tracking protocol, 81 patients treated at a single center between with proton beam therapy completed the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before treatment and at the follow-up examinations. We reviewed the dosimetric data, reported as Vx (volume of organ receiving x Gy), and patient-reported QOL at 6 months. Genitourinary QOL was assessed using the American Urological Association symptom score and EPIC urinary domain score. GI QOL was assessed using the EPIC GI domain score.Larger prostate glands were associated with greater bladder V70 (P < .01) and rectal V70 (P < .01). The rectal V70 was < 15% for all patients (range, 4%-13.8%) with the planned treatment volume coverage (percentage of the prescription dose covering 95% of the volume > 95%) maintained. Patients with larger prostates did not have a greater change in their American Urological Association symptom index scores (< 30 cm3, +2.3; 30-49 cm3, +3.2; ≥ 50 cm3, 0.2; P = .06) or urinary domain score (< 30 cm3, −3.6; 30-49 cm3, −3.1; ≥ 50 cm3, +3.8; P = .76) at 6 months after treatment. Also, prostate size was not associated with a change in the EPIC GI domain score at 6 months after treatment (< 30 cm3, −3.7; 30-49 cm3, −1.1; ≥ 50 cm3, −0.55; P = .67).Definitive proton beam therapy for prostate cancer to a dose of 79.2 Gy resulted in excellent patient-reported urinary and GI QOL, independently of the baseline prostate size. This single-institution finding should be tested further in a multi-institutional study to confirm the potential limited role of androgen deprivation therapy.