Background: p53 is one of the most common genetic aberrations in human cancer and is associated with poor outcomes with hormone therapy in advanced prostate cancer (PCa). p53 is a well-established predictor of biochemical relapse in PCa, however, increasing evidence from ICECaP has demonstrated that metastatic relapse (MR) not biochemical relapse (BCR) is a surrogate for prostate-cancer specific mortality (PCSM). Furthermore, there are now a range of novel therapeutic strategies targeting p53 mutations and their downstream effector pathways. This study aimed to assess the association between p53 expression and MR/PCSM in men with localized PCa. Methods: The study consisted of 271 men with localized PCa treated with radical prostatectomy. Surgical cancer specimens were stained for p53 by immunohistochemistry (IHC) and scored as a) percentage of p53-positive tumor nuclei in all major foci of cancer within the prostate; and (b) clustering, where the presence of 12 or more p53-positive cells within a x200 power field was deemed “cluster positive”. Results: At a median follow-up of 15.8 years (range 4 months - 24.3 years), 57.5% (156/271) had a biochemical relapse, 18% (49/271) had suffered a metastatic relapse, and 9.5% (25/271) had died of prostate cancer. Increasing percentage of p53 positive nuclei was significantly associated with shorter time to BCR (p < 0.001), MR (p < 0.001) and PCSM (p < 0.001). Half of patients were p53 cluster positive. P53 cluster positivity was significantly associated with all clinical endpoints (BCR: HR 2.0, 95% CI 1.51-2.65, p < 0.001; MR: HR 4.1, 95%CI 2.02-8.14, p < 0.001; PCSM: HR 12.2, 95%CI 1.6-93; p = 0.016). These associations were independent of other established prognostic variables including lymph node status, baseline PSA, Gleason and ISUP grade on multivariable analysis. Conclusions: This study has confirmed the association of p53 in radical prostatectomy tissue with clinically relevant endpoints of metastatic relapse and prostate cancer specific mortality. p53 is a potential stratification factor and may be useful for identifying those who will most benefit from adjuvant therapy. Incorporation of p53 status into ongoing clinical trials is now warranted.