Although familial and dietary factors are recognized as important risk determinants for colorectal tumorigenesis, the specific causes of colorectal cancer remain unclear. Studies of p53 genetic alterations have provided clues concerning the etiology of many cancers. This study was designed to determine whether overexpression of the p53 protein is associated with familial and dietary risk factors. Epidemiological data were obtained from 163 colorectal cancer cases and 326 healthy controls. Tumors of all patients were analyzed immunohistochemically for p53 overexpression using an avidin-biotin immunoperoxidase procedure and polyclonal anti-p53 antibody CM1. Of patient tumors, 44.8% showed p53 nuclear reactivity. Colorectal cases versus controls were three times more likely to report a family history of colorectal cancer [odds ratio (OR), 3.12; 95% confidence interval (CI), 1.77-5.52]. Only cruciferous vegetables exhibited a significant inverse association (OR, 0.59; 95% CI, 0.34-1.02; trend test, P = 0.03) for the highest versus lowest quartiles. Both meat and beef displayed an elevated increase in risk. When cases with p53 overexpression (p53 positive) were compared with cases without p53 overexpression (p53 negative), etiological heterogeneity was suggested for family history of colorectal cancer (OR, 0.39; 95% CI, 0.16-0.93), cruciferous vegetables (trend test, P = 0.12), and beef consumption (trend test, P = 0.08). To estimate the individual relative risks for p53-dependent and p53-independent pathways, each p53 subtype was compared with controls. Cruciferous vegetables exhibited a significant association (OR, 0.37; 95% CI, 0.17-0.82; trend test, P = 0.03) when p53 positive cases were compared with controls. When p53 negative cases were compared with controls, a significant increase in risk was observed for family history of cancer (OR, 4.46; 95% CI, 2.36-8.43) and beef (OR, 3.17; 95% CI, 1.83-11.28; trend test, P = 0.006). The p53 (positive) dependent pathway was characterized by an inverse association with cruciferous vegetables, and p53-independent tumors were characterized by family history and beef consumption. These data may indicate the significance of linking epidemiology and molecular biology in assessing specific etiological pathways.