Background: The race/ethnicity based research in colorectal cancer (CRC) care continues to remain a high priority in developing personalized medicine, and to improve overall clinical outcomes. The role of p53 abnormalities in prognostication of CRC has been evaluated earlier. The incidence of nuclear accumulation of p53 (p53^nac) and its prognostic relevance in African American (AA) and non-Hispanic white patients (pts) have been investigated, and it was suggested that the clinical consequences of p53^nac in CRC varies with anatomic location of the tumor and the race of the patient. However, the clinical value of p53^nac in relation to age, the tumor location, and race together is not assessed. Thus, we evaluated prognostic significance of p53^nac by considering the tumor location, age, race/ethnicity and p53^nacin CRCs in AA and white pts. Methods: Formalin fixed paraffin embedded CRC tissues from 242 AAs and 346 whites who underwent surgery were assessed for p53^nac by routine immunohistochemistry (IHC). The routine (not antigen retrieval) IHC will identify the majority of genetic alterations ( > 95% missense point mutations) and have significant association with patient survival in CRC. The association between phenotypes, p53^nacstatus, clinicopathologic features, and overall survival were evaluated using the x² test and Cox regression analyses. Results: Approximately equivalent proportions of distal (52%) and proximal adenocarcinomas (48%) were positive for p53^nac in AA pts. In contrast, distal CRC from whites more frequently were positive for p53^nac than from the proximal colon (67% vs. 34%, x² P = 0.006). p53^nac was found to be a strong predictor of poor overall survival in young ( < 65 yr) white pts with proximal tumors [hazard ratio (HR) = 2.8, 95% Confidence Intervals (CI):1.2-6.4] but not in AAs (HR = 0.7, 95% CI: 0.41-1.21). Conclusions: The findings of this study suggest that p53^nac is a strong prognostic marker for young white pts with proximal colon adenocarcinomas. Our findings are clinically relevant because several small-molecule inhibitors of mutant p53 are under investigation. These studies were supported by a pilot project grant by the UAB Comprehensive Cancer center.