Abstract The purpose of this retrospective study was to compare the toxicity and disease control rate of radiotherapy for prostate cancer in salvage settings after high-intensity focused ultrasound (HIFU) therapy (HIFU cohort) with those in radical settings (non-HIFU cohort). From 2012 to 2020, 215 patients were identified for this study and 17 were treated in the salvage settings after HIFU. The median follow-up time was 34.5 months (range: 7–102 months, inter-quartile range IQR: 16–64 months). Genitourinary (GU) and gastrointestinal (GI) adverse events were evaluated in acute and late periods with Common Terminology Criteria for Adverse Events version 5, and the rates of biochemical-clinical failure free survival (BCFS) and overall survival (OS) were estimated. The cumulative incidence of late GU Grade 2 or greater toxicity after five years was significantly different between the non-HIFU and HIFU cohorts with rates of 7.3% and 26.2%, respectively (P = 0.03). Regarding GI Grade 2 or greater toxicity, there was no significant difference between the two cohorts. The 5y-BCFS was 84.2% in the non-HIFU cohort and 69.5% in the HIFU cohort with no significant difference (P = 0.10) and the 5y-OS was 95.9% and 92.3%, respectively (P = 0.47). We concluded that the possibility of increased late GU Grade 2 or greater should be considered when applying salvage radiotherapy for local recurrence after HIFU.