Purpose: To evaluate the effect of prostate volume on outcomes after moderately hypofractionated radiation therapy (mHFRT) for prostate cancer. Methods and Materials: Prostate cancer patients treated with mHFRT at a Veteran's Affairs Medical Center from August 20, 2008, to January 31, 2018, were identified. Patients were placed into a large prostate planning target volume (LPTV) cohort if their prostate PTV was in the highest quartile. Acute/late genitourinary (GU) and gastrointestinal toxicity events among patients with and without LPTV were compared. Multivariable analyses estimated the effect of factors on toxicity. Overall survival, biochemical recurrence-free survival, and freedom from late GU/gastrointestinal toxicity of patients with and without LPTV were estimated via Kaplan-Meier. Results: Four hundred and seventy-two patients were included. Ninety-three percent received 70 Gy in 2.5 Gy fractions; 75% received androgen deprivation therapy. Median follow-up was 69 months. Patients with LPTV (PTV >138.4 cm3) had a higher late 2 + GU toxicity compared with those without (59% vs 48%, P = .03). Earlier time to late 2 + GU toxicity was associated with LPTV (hazard ratio 1.36; 95% confidence interval [CI], 1.00-1.86; P = .047), androgen deprivation therapy use (hazard ratio 1.60; 95% CI, 1.13-2.27; P = .01), and higher baseline American Urologic Association symptom score (odds ratio 1.03; 95% CI, 1.02-1.05; P < .001). At 2 years, freedom from late 2 + GU toxicity was 46% (95% CI, 47%-54%) for those with LPTV versus 61% (95% CI, 55%-65%) for those without (P = .04). Late grade 3 GU toxicity was 7% for those with LPTV and 4% for those without. No differences in overall survival or biochemical recurrence-free survival were observed between patients with or without LPTV. Conclusions: LPTV did not affect efficacy of mHFRT for prostate cancer; however, it was associated with increased risk and earlier onset of late grade 2 + GU toxicity.