Background The impact of salvage radiotherapy (SRT) and its timing on health-related quality of life (HRQoL) in prostate cancer patients is still unclear. Objective To compare the HRQoL of patients who underwent SRT with that of patients who underwent radical prostatectomy (RP) only and to investigate whether SRT timing is associated with HRQoL. Design, setting, and participants All SRT patients (n = 241) and all RP-only patients (n = 1005) were selected from a prospective database (2004–2015). The database contained HRQoL and prostate problem assessments up to 2 yr after last treatment. Outcome measurement and statistical analysis Mixed effects growth modelling adjusting for significant differences in patient characteristics and baseline HRQoL was used to analyze the association between: (1) “treatment” (RP-only vs SRT) and (2) “timing of SRT” with changes in HRQoL. Results and limitations SRT patients showed significantly (p