Focal adhesion kinase (FAK) is overexpressed in a number of tumors, including breast cancer. Another marker of breast cancer tumorigenesis is the tumor suppressor gene p53 that is frequently mutated in breast cancer. In the present study, our aim was to find a correlation between FAK overexpression, p53 expression and mutation status in a population-based series of invasive breast cancer tumors from the Carolina Breast Cancer Study. Immunohistochemical analyses of 622 breast cancer tumors revealed that expression of FAK and p53 were highly correlated (p = 0.0002) and FAK positive tumors were 1.8 times more likely to be p53 positive compared to FAK negative tumors [odds ratio (OR) = 1.8; 95% Confidence Interval (CI) 1.2-2.8, adjusted for age, race and stage at diagnosis]. Tumors positive for p53 expression showed higher intensity of FAK staining (p < 0.0001) and higher percent of FAK positive staining (p < 0.0005). From the same study, we evaluated 596 breast tumors for mutations in the p53 gene, using single strand conformational polymorphism and sequencing. Statistical analyses were performed to determine the correlation between p53 mutation status and FAK expression in these tumors. We found that FAK expression and p53 mutation were positively correlated (p < 0.0001) and FAK positive tumors were 2.5 times more likely to be p53 mutation positive compared to FAK negative tumors [adjusted OR = 2.5, 95% CI 1.6-3.9]. This is the first analysis demonstrating a high correlation between FAK expression and p53 mutations in a population-based series of breast tumors.