Purpose: This retrospective study aims at investigating the effects of moderately hypofractionated radiation therapy (HRT) on acute and late toxicities as well as on early biochemical control and therapeutic efficiency compared to conventional radiation therapy (CRT) in prostate cancer. Patients and methods: We analyzed 55 HRT patients irradiated with the total dose of 60 Gy in 20 fractions delivered over 4 weeks. These patients were compared to a control group of 55 patients who received CRT with a total of <78 Gy in 37–39 fractions delivered over circa 8 weeks. External beam radiation therapy (EBRT) was conducted using daily image-guided (cone beam CT) volumetric modulated arc therapy (VMAT) and a simultaneously integrated boost (SIB) for both groups to protect the rectum. Acute toxicities were evaluated according to Common Terminology Criteria for Adverse Events (CTCAE) v5, whereas chronic toxicities were assessed in accordance with LENT-SOMA. Patient traits were compared by implementing t‑tests and Wilcoxon–Whitney tests for continuous variables, whereas discrete characteristics were evaluated by applying two-tailed Fisher’s exact tests. In addition, we calculated average treatment effects (ATE). Thereby, propensity score matching (PSM) based on nearest-neighbor matching considering age, comorbidities, and risk stratification as covariates was applied. The statistical analysis was conducted using Stata 14.2 (StataCorp LLC, TX, USA). Results: As confirmed by the descriptive tests, the ATE revealed that the intensity and occurrence of urinary frequency (p = 0.034) and proctitis (p = 0.027) significantly decreased for the HRT group, whereas all other acute toxicities did not differ significantly between the HRT and CRT groups. For late toxicities, neither statistical tests nor ATE estimation showed significant differences. Also, no significant difference was found regarding the decrease in prostate specific antigen (PSA) after a median follow-up of 13 months (range 2–28 months), which indicates biochemical freedom from progression. Conclusion: HRT offers several medical and economic advantages and should therefore be considered as a useful alternative to CRT.