Background: Increased utilization of next-generation sequencing has revealed evidence of early TP53 alterations in localized prostate cancer (PCa), suggesting a growing clinical potential for p53 immunohistochemistry (IHC). Prior research by Harmon and Gesztes et al. (Radiology, 2021 & Scientific Reports, 2022) support the clinical utility of detecting p53 overexpression in core biopsies and radical prostatectomies (RP) to predict underlying TP53 alterations, biochemical recurrence (BCR), and metastasis. However, to date, no established consensus exists evaluating p53 “overexpression” in PCa. This study aimed to compare two fundamental approaches to assess p53 expression across various specimens with regard to PCa progression. A secondary study aim explored whether ethnic differences in p53 expression exist. Methods: This retrospective cohort study comprised 84 randomly selected PCa patients (46 metastatic; 38 non-metastatic) enrolled between 1996 – 2021 at the DC VA Medical Center. Representative sections of core biopsies (60%), RP (17%), prostate chips (7%), and metastatic deposits (16%) were examined, where (%) equals a share of the total cohort. IHC was performed on selected sections with a p53 monoclonal antibody (Biocare Medical; p53 Tumor Suppressor Protein; clone DO-7). p53 nuclear expression was manually scored according to the highest intensity (0 absent, 1+ weak, 2+ moderate, or 3+ marked) and percentage (0%, <1%, 1-5%, and >5%) of tumor cell nuclei observed in one index block per patient. All slides were reviewed by two pathologists who were blinded to clinical data. Fisher’s exact test was used to test the association between p53 positivity and categorical variables. Results: Of 84 men included, 63 (75%) self-identified as African American (AA). The median follow-up time was 6.2 years. Thirty-four patients (40%) exhibited p53 nuclear expression, of which 18 patients (21%) showed marked (3+) nuclear intensity. Notably, 11 of 18 (61%) 3+ patients displayed <5% p53 expression. All patients with >5% p53 positivity showed marked (3+) p53 staining. The presence of marked p53 staining, regardless of percentage, was found to be significantly associated with a higher Gleason score (p=0.0002), higher PSA at the time of biopsy (p<0.0001), BCR (p=0.0007) and metastasis (p<0.0001). Importantly, marked p53 staining was identified only in patients who developed metastatic disease. No significant differences were observed in marked p53 expression between AA and Caucasian men. Conclusions: In prostate cancer, marked (3+) p53 nuclear intensity (regardless of the percentage) is associated with disease progression with no observable ethnic predilection. Therefore, careful assessment of intensity is essential to avoid under-detection (when percent criteria are applied) and maximize the number of patients who may benefit from enhanced clinical interventions.