Background Local occurrence of prostate cancer (PCa) after external beam radiation (EBRT) may benefit from definitive local therapy. Objective To evaluate the safety and efficacy of salvage high-intensity focal ultrasound (HIFU) in local PCa recurrence after EBRT and to determine prognostic factors for optimal patient selection. Design, Setting, and Participants Between 1995 and 2006, patients with a local PCa recurrence after EBRT were retrospectively included. Intervention All patients received salvage HIFU with the Ablatherm device. Measurements Prognostic factors (pre-EBRT risk group, androgen-deprivation [AD] use, pre-HIFU prostate-specific antigen [PSA], Gleason score and positive biopsy percentage) were studied in univariate and multivariate analyses. Progression was defined as positive biopsy and/or last PSA > nadir+2 ng/ml and/or adjuvant therapy introduction. All complications were recorded. Results and Limitations Some 194 HIFU sessions for 167 patients were performed. Local cancer control was achieved with negative biopsy results in 122 (73%) patients. The median PSA nadir was 0.19 ng/ml. The mean follow-up period was 18.1 months (range: 3–121 mo). Seventy-four patients required no hormone therapy. The actuarial 5-year overall survival rate was 84%. The actuarial 3-yearr progression-free survival rate was significantly lower in 3 circumstances: (1) worsening of the pre-EBRT stage with 53%, 42%, and 25% for low-, intermediate-, and high-risk patients, respectively, (2) increase in the pre-HIFU PSA, and (3) use of AD during PCa management. In multivariate analyses, the risk ratio for intermediate- and high-risk patients were 1.32 and 1.96, respectively. The risk ratio was 2.8 if patients had received AD. No rectal complications were observed. Urinary incontinence accounted for 49.5% of the urinary sphincter implantations required in 11% of patients. This is a retrospective study in which the role of the PSA doubling time and the time until recurrence was not evaluated. Conclusions Salvage HIFU is a curative treatment option for local relapse after EBRT with acceptable morbidity. Careful patient selection is imperative depending upon the aforementioned prognostic factors.