Background: Although multiple Phase I/II studies demonstrate safety and low rates of toxicity following stereotactic body radiotherapy (SBRT) to the intact prostate, there are limited data on hypofractionation and SBRT after prostatectomy. This Phase I study was performed to evaluate acute toxicity associated with dose escalation from 3.6 Gy per fraction to 7.1 Gy per fraction to the prostate bed in the post-prostatectomy treatment of prostate cancer. We hypothesize that the toxicity of escalating the dose per fraction to the prostate fossa in the post-operative setting will be well tolerated; and we expect toxicity to be comparable to normal fractionation schedules. Methods: This study (NCT02446366) was designed to look at acute toxicity, defined as toxicity that occurred within the first 10 weeks of RT, of different dose fractionation schemes in the post-prostatectomy setting. The doses chosen for dose escalation on this study are based on an equivalent biological effective dose to a previously published hypofractionated post-prostatectomy study that showed no increase in acute bowel or bladder toxicity. The dose levels are as follows: Level 1 -3.6 Gy x 15 fractions; Level 2- 4.7 Gy x 10 fractions; Level 3 - 7.1 Gy x 5 fractions. Eligibility for participation on the trial was for patients who had pT3N0 disease regardless of margin status in the post-prostatectomy setting, pT2N0 patients with positive margin or with a negative surgical margin and a rising post-operative PSA. Patients could be on concurrent ADT and enroll on this study. Dose was escalated according to a 6+6 schema. For purposes of deciding whether to escalate to a new dose level, expand a dose level or de-escalate from a dose level, we used toxicities and adverse events that occur during the 1^st 10 weeks after completion of radiotherapy. Six patients were enrolled on each new dose level with a total of 12 patients required at the maximum tolerated dose. Dose-limiting toxicity (DLT) was defined as grade 3 or worse fatigue, gastrointestinal (GI) or genitourinary (GU) toxicity by Common Terminology Criteria of Adverse Events (version 4.03). Dose levels 1 and 2 have been completed without any DLT. Dose level 3 has enrolled 9/12 patients without any DLT. Clinical trial information: NCT02446366