PurposeThe aim of this study was to assess the toxicity and outcomes following treatment of prostate cancer with seminal vesicle involvement (SVI) evident on magnetic resonance imaging or clinical examination with moderately hypofractionated radiation therapy (MHRT).Methods and MaterialsForty-one patients treated with MHRT to the prostate and 1 or both seminal vesicles from 2013 to 2021 at a single institution were identified and propensity score matched to 82 patients treated during the same period with prescription dose given to the prostate alone. Dosimetry of the planning target volume, bladder, and rectum were compared. Urinary and bowel toxicity were scored by National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Clinical outcomes including freedom from biochemical recurrence, prostate cancer–specific survival, and overall survival were assessed.ResultsOf the 41 patients identified with SVI, 26.8% had SVI by clinical examination and 95.1% had high-risk prostate cancer. Compared with the cohort without SVI, treatment plans to include SVI had a larger planning target volume (152.2 vs 109.9 cc;P< .001), maximum point dose (107.9% vs 105.8%;P< .001), and volume receiving 100% of the prescription dose (143.1 vs 95.9 cc;P< .001). No difference in bladder dosimetric variables between cohorts was observed, but there was an increase in the rectal maximum point dose (103.9% vs 102.8%;P= .030) and rectal volume receiving 100% of the prescription dose (1.8 vs 1.2 cc;P= .016). Despite these differences, there was no difference in the cumulative incidence of grade 2+ urinary (hazard ratio [HR], 0.73; 95% CI, 0.39-1.35;P= .31) or bowel (HR, 0.35; 95% CI, 0.04-3.03;P= .34) toxicity. Freedom from biochemical recurrence (HR, 0.47; 95% CI, 0.16-1.38;P= .17), prostate cancer–specific survival (HR, 0.31; 95% CI, 0.04-2.49;P= .31), and overall survival (HR, 0.35; 95% CI, 0.10-1.16;P= .09) also did not differ with or without SVI, respectively.ConclusionsTreatment of SVI to prescription dose with MHRT for localized prostate cancer does not increase bowel or urinary toxicity. Similar clinical outcomes were also observed with or without SVI.