OBJECTIVE To evaluate whether hypofractionation is well tolerated and to preliminarily assess biochemical control of this regimen in a postprostatectomy, salvage setting. METHODS A retrospective analysis was performed in 50 patients treated between May 2003 and December 2005 with hypofractionated radiotherapy for biochemical recurrence after radical prostatectomy. Radiotherapy was prescribed to the prostatic fossa to 65-70 Gy in 26-28 fractions of 2.5 Gy each, using intensity-modulated radiotherapy with daily image localization. Toxicities were scored using a modified Radiation Therapy Oncology Group scale and the Fox Chase modification of Late Effects Normal Tissue scale. The median follow-up was 18.9 months (range, 5.3-35.9). RESULTS No Grade 3 or greater acute or late toxicities were observed. Grade 2 toxicities included four acute genitourinary, one acute gastrointestinal, two late genitourinary, and two late gastrointestinal toxicities. Of the 50 patients, 39 demonstrated a continuous biochemical response after salvage therapy, 3 had an initial response before prostate-specific antigen failure, and 7 had prostate-specific antigen progression, 1 of whom died of progressive metastatic disease. Finally, 1 patient discontinued therapy because of the diagnosis of a metachronous pancreatic cancer and died without additional prostate cancer follow-up. All remaining patients were alive at the last follow-up visit. A lower presalvage prostate-specific antigen level was the only significant prognostic factor for improved biochemical control. The estimated actuarial biochemical control rate at 2 years was 72.9%. CONCLUSIONS The toxicity and early biochemical response rates were consistent with expectations from conventional fractionation. Additional follow-up is required to better document the biochemical control, but these results suggest that hypofractionation is a well-tolerated approach for salvage radiotherapy.