Background: Several surrogates for prostate cancer-specific mortality exist, but whether these are surrogates for all cause mortality (ACM), and how their performance compares, is unknown. We investigated the relative efficacy of 4 candidate surrogates for ACM using the proportion of treatment effect (PTE) metric. Methods: Two-hundred and six men with localized unfavorable-risk prostate cancer were randomized to radiation therapy (RT) or RT and 6 months of androgen-deprivation therapy (ADT) from 1995 to 2001 and followed for a median of 16.62 years. Among the 159 men with no or minimal comorbidity, a significant reduction in the risk of death was observed in those randomized to RT and ADT versus RT alone; these 159 men formed the study cohort. In order to assess whether the candidate surrogated satisfied Prentice’s criteria for surrogacy, Cox regression analyses were performed to assess the risk of death for each of the candidate surrogates and treatment before and after adjusting for prostate-specific antigen (PSA), age at randomization, T category, and Gleason score. Results: PSA nadir > 0.5 ng/mL, PSA doubling time < 9 months and interval to PSA failure < 30 months met Prentice’s criteria for surrogacy (P = 0.01, 0.003, and 0.03 for the surrogate covariate in the multivariable model, respectively) for ACM, while PSA failure did not (P = 0.10). For the three surrogates, the PTE values were 103.86%, 43.09%, and 41.26%, respectively. Conclusions: A PSA nadir value of > 0.5 ng/mL following RT and ADT identified men prior to PSA failure who were at high-risk for death and therefore could be used to select men for entry, at the time of PSA nadir and before PSA failure, onto randomized trials evaluating the impact on survival of salvage ADT with or without agents shown to prolong survival in men with castrate-resistant metastatic prostate cancer. By enriching study cohorts with men who have achieved a surrogate endpoint for ACM, one can enhance the likelihood that the study will be able to observe whether survival is prolonged when novel treatment is added to ADT, as compared to ADT alone, in an abbreviated time period. Clinical Trial Number: NCT00116220