Background: To identify post-operative prostate cancer patients who are unlikely to achieve long-term biochemical control following salvage radiotherapy (SRT). We hypothesize that patients with node-positive disease, no nadir after radical prostatectomy (RP), or a high pre-radiotherapy (pre-RT) PSA levelwill have a low chance of benefitting from SRT. Methods: Ninety patients who received SRT following RP were retrospectively analyzed to determine factors associated with biochemical failure. Patients on continuous androgen deprivation therapy (ADT) were excluded from statistical analysis. Results: Median follow-up was 30 months (range 6-120). The overall projected 3-year bPFS was 70%. Factors significantly associated with biochemical failure on univariate analysis included Gleason score, positive seminal vesicle invasion, PSA doubling time of 6 months or less, and pre-RT PSA greater than 1.0 ng/mL. All patients with a pre-RT PSA greater than 3.0 ng/mL failed. Patients who did not reach an undetectable nadir following RP had 55% 3-year bPFS compared with 79% in those who did achieve an undetectable PSA (p=0.041). Multivariate analysis demonstrated that GS of 8 and pre-RT PSA were significant predictors. A separate analysis was performed on a subgroup of 8 patients with node-positive disease. Five patients failed at a median of 24 months (range 12-64). Of the remaining 3 patients, 2 had been maintained on long-term ADT, and 1 patient was 11 months out from treatment. Conclusions: Patients with node-positive disease are unlikely to achieve long-term biochemical control from SRT due to extra-prostatic disease spread. Although various factors may influence outcome, no other group demonstrated a very low chance of benefit. Patients with rising PSA benefit from early treatment before PSA rises above 1.0 ng/mL.