Purpose: We sought to determine the optimal hypofractionated regimens of moderately hypofractionated (HFRT) versus conventionally fractionated (CFRT) external beam radiotherapy for localized prostate cancer (LPCA), having as primary endpoints the 5-year biochemical failure (BF) and late gastrointestinal (GI) and genitourinary (GU) toxicity. Methods and materials: We performed a systematic literature review of the Medline and National Library of Medicine databases according to the PRISMA guidelines. Only phase III trials of CFRT versus moderate HFRT for LPCa, reporting 5-year BF and/or minimum 3-year late ≥G2 toxicity rates were considered. Results: A total of 11 manuscripts reporting the outcomes of 8145 patients gathered from 9 randomized trials met the eligibility criteria. No significant difference between CFRT and HFRT was found in any of the investigated outcome measures. 80%, 15% and 29% isolevel curves for freedom from BF (FFBF), GI and GU toxicity, respectively, resulting from grouping the median values of all endpoints, were calculated as a function of both total dose (Dtot) and dose per fraction (d). Trials using fractionation schedules (d × n) lying above the FFBF and below toxicity isolevels are expected to produce the best therapeutic ratio. Conclusions: Our analysis indicates an optimal therapeutic window within which Dtot, d and n can be safely adjusted. Owing to both the risks of uncertainty due to inclusion of trials with d up to 3.5 Gy, and the exploitation of different cell killing mechanisms associated to larger d, the extrapolation to extremely hypo-fractionated regimens is not warranted.