The impact of salvage radiotherapy (SRT) on overall survival (OS) in patients experiencing biochemical recurrence (BCR) of prostate cancer remains an area of active investigation. The international multicenter PROMISE registry provides a valuable dataset to explore the association between SRT and long-term clinical outcomes in this patient population (NCT06320223). Methods: Comprehensive restaging at the time of BCR was performed by integrating both serologic markers and advanced molecular imaging (PET/CT or PET/MRI), offering an accurate assessment of molecular imaging (mi) TNM stage. Results: In total, 1410 patients experiencing BCR with prior prostatectomy were included. The median follow-up was 5.2 y (interquartile range, 3.8–6.9 y). SRT was administered after PET to 381 of 680 patients (56.0%) with PET-negative disease (miT0N0M0) and to 478 of 730 patients (65.0%) with PET-locoregional disease (miT/N1 M0). SRT was associated with longer OS in the entire cohort (hazard ratio, 0.66; 95% CI, 0.47–0.93; P 5 0.019) with 5- and 7-y survival rates of 95.2% (95% CI, 93.6%–96.8%) and 90.8% (95% CI, 88.1%–93.6%), respectively. Without SRT, 5- and 7-y survival rates were 92.1% (95% CI, 89.6%–94.7%) and 83.8% (95% CI, 79.8%–88.1%), respectively. Subgroup analysis found significant benefit for patients with miT0N0M0 disease (hazard ratio, 0.42; 95% CI, 0.22–0.78; P 5 0.0061), particularly those with a prostate-specific antigen level of 0.5 ng/mL or lower (P 5 0.03, log-rank test). Conclusion: SRT improves OS for patients with BCR, especially those with a negative prostate-specific membrane antigen–targeted PET.