Whole pelvis (WP) radiation therapy (XRT) significantly improved biochemical relapse free survival (bRFS) compared to prostate-bed (PB)-only XRT in RTOG 0534, yet increased toxicity and was performed in an era prior to PET staging (Pollack et al, Lancet, 2022). Separately, 18F-fluciclovine PET/CT (PET)-guided post-prostatectomy XRT demonstrated improved bRFS compared to XRT guided by conventional imaging alone. We hypothesized that patients whose decisions were changed from whole pelvic XRT to PB-only XRT after PET imaging would have bRFS that was (a) not significantly different than patients initially planned for PB-only XRT, and (b) significantly improved over patients planned for WP XRT without PET guidance. We conducted a post-hoc analysis of a prospective, randomized, single-institution trial comparing conventional (Arm A) v. PET-guided (Arm B) post-prostatectomy XRT. For patients randomized to Arm B, pre-PET treatment field decisions were recorded, and post-fluciclovine fields were rigidly defined per protocol: pN0 patients with no pelvic or extrapelvic PET uptake received PB-only XRT. Three- and four-year bRFS were compared in patients initially planned for WP with change to PB-only XRT [Arm B (WP→PB)] v Arm B patients initially planned for PB-only with final XRT to PB-only [Arm B(PB→PB)] & Arm A patients treated with whole pelvic XRT [Arm A(WP)] using Z test and log-rank test. Demographics were compared using Chi-square test, Fisher's exact test, or ANOVA as appropriate. We identified 10 Arm B (WP→PB), 31 Arm B (PB→PB), and 25 Arm A (WP) patients. Androgen deprivation was used in 50.0% of Arm B (WP→PB) and 3.2% of Arm B (PB→PB) patients, p<0.01. Mean pre-XRT PSA was significantly higher (1.56 v 0.32 ng/mL, respectively, p<0.01) in Arm B (WP→PB) v Arm B (PB→PB) patients, however, there was no significant difference in extracapsular extension (p = 1.00), seminal vesical invasion (p = 1.00), Gleason score ≥8 (p = 0.58) or margin positivity (p = 0.73) between cohorts. Three- and four-year bRFS was 80% in Arm B (WP→PB) & 87.4% in Arm B (PB→PB), p = 0.47, respectively. Arm A (WP) patients had significantly worse three- (35.2%) and four-year (13.2%) bRFS compared to Arm B (WP→PB), p<0.01. Patients initially planned for WP XRT whose treatment field decisions were changed to PB-only XRT after PET guidance had, in this post-hoc analysis, (a) relapse rates not significantly different than patients initially planned for PB-only XRT and (b) improved relapse rates over patients treated with WP XRT without PET guidance. PET-guided volume de-escalation in selected patients may be one approach to mitigating excess toxicity seen with WP XRT without compromising outcomes and warrants further exploration.