Background: Salvage radiation therapy (SRT) is a recommended treatment option for biochemical recurrence after radical prostatectomy (RP). However, its effectiveness may be limited to specific categories of patients. Objective: We aimed to identify the optimal candidates for early SRT after RP. Design, setting, and participants: The study included 925 node-negative patients treated with SRT after RP at seven institutions. Patients received SRT for either prostate-specific antigen (PSA) rising, or PSA persistence after RP that was defined as PSA level ≥0.1 ng/ml at 1 mo after surgery. All patients received local radiation to the prostate and seminal vesicle bed. Outcome measurements and statistical analysis: The primary outcome measured was distant metastasis after SRT. Regression tree analysis was used to develop a risk-stratification tool. Multivariable Cox regression analysis and nonparametric curve fitting methods were used to explore the relationship between PSA level at SRT and the probability of metastasis-free survival at 8 yr. Results and limitations: At a median follow-up of 8.0 yr, 130 patients developed distant metastasis. At multivariable analysis, pre-SRT PSA level was significantly associated with distant metastasis (hazard ratio: 1.01, p <. 0.0001). However, when patients were stratified into five risk groups using regression tree analysis (area under the curve: 85%), early SRT administration provided better metastasis-free survival in three groups only: (1) low risk: undetectable PSA after RP, Gleason score ≤7, and tumour stage ≥pT3b, (2) intermediate risk: undetectable PSA after RP with Gleason score ≥8, (3) high risk: PSA persistence after RP with Gleason score ≤7. Conclusions: We developed an accurate risk stratification tool to facilitate the individualised recommendation for early SRT based on prostate cancer characteristics. Early SRT proved to be beneficial only in selected groups of patients who are more likely to be affected by clinically significant but not yet systemic recurrence at the time of salvage treatment administration. Patient summary: In patients affected by prostate cancer recurrence after radical prostatectomy, the early administration of salvage radiation therapy is beneficial only for selected subgroups of patients. In this study, these groups of patients were identified. In this multi-institutional study, we developed a prognostic tool to assess the risk of distant metastases after early salvage radiation therapy for prostate-specific antigen (PSA) rise after prostatectomy. Five distinct risk groups were identified based on clinical and pathological characteristics. Early salvage radiation therapy administration was noted to be associated with improved cancer control for low-, intermediate-, and high-risk patients. Conversely, very low-risk (undetectable PSA after radical prostatectomy, Gleason score ≤7, and tumour stage ≤pT3a) and very high-risk patients (PSA persistence after radical prostatectomy, and Gleason score ≥8) did not benefit from early salvage treatment. These findings facilitate the identification of optimal candidates for early salvage radiation therapy, and, pending validation, application into clinical practice will help to maximise cancer control while avoiding overtreatment. © 2017 European Association of Urology.