© 2015 American Society for Radiation Oncology. Purpose: The purpose of this study was to determine whether radiation dose inhomogeneity within the prostate predisposes to late urinary strictures after moderately hypofractionated definitive external beam radiation therapy for prostate cancer. Methods and materials: One hundred seventy-three men with clinically localized prostate cancer met the inclusion criteria for this analysis. All patients received 70 Gy to the prostate delivered over 28 fractions, had at least 2 years of clinical follow-up, and had dose-volume histogram information available for review. The endpoint of this study was the development of a urethral stricture that required a procedural intervention such as urethral dilation or suprapubic catheterization. Dosimetric parameters were evaluated for effect on the rate of urethral stricture formation by univariate Cox proportional hazards modeling. Results: The median follow-up was 49.5 months (range, 24.6-108 months). At 5 years, the actuarial rate of intervention for urethral strictures across all patients was 4.9%. The maximum point dose within the prostate (P = .034, hazard ratio = 1.006) and the mean prostate dose (P = .039, hazard ratio = 1.004) were the only parameters predictive of urethral stricture formation. All patients who developed a urethral stricture were treated by a plan with a maximum prostate dose of > 75 Gy (median, 77.67 Gy). Conclusions: For patients receiving moderately hypofractionated prostate radiation therapy over 28 fractions, a maximum point dose of 75 Gy within the prostate was associated with an increased probability of developing a urethral stricture that required procedural intervention. The hypothesis that hypofractionation increases susceptibility to toxicity from heterogeneity within the prostate should be confirmed by analyzing data from randomized trials with a conventionally fractionated control arm for comparison.