The regulation of the epidermal growth factor receptor (egfr) gene in human cancer is not yet fully understood. Recent data on a polymorphic CA repeat located at the 5'-regulatory sequence in intron 1 of the egfr gene [egfr CA simple sequence repeat (SSR) I] point to a possible inheritance of cancer risk associated with the egfr gene. Furthermore, we have detected frequent allelic imbalances restricted to the egfr CA SSR I in breast cancer tissue and nontumorous breast tissue adjacent to invasive and in situ breast cancer representing amplifications. Therefore, we conducted a population-based case-control study to assess the relationship between the egfr polymorphism and breast cancer risk. Cases with a first primary breast cancer by age 50 years and age-matched population controls provided information on known and suspected risk factors. The allelic length of the egfr CA SSR was determined in 616 cases and 1072 population-sampled controls. Genotypes were categorized for analysis by allele length. Multivariate logistic regression was used to compare genotype distributions, accounting for other risk factors, and to investigate gene-environment interactions. We found a modifying effect, albeit no main effect, of the allelic length of the egfr polymorphism on breast cancer risk. The presence of two long alleles (>/==" BORDER="0">19 CA) was associated with a significantly elevated odds ratio (OR) of 10.4 [95% confidence interval (CI), 1.85-58.70] among women with a first-degree family history of breast cancer (P = 0.015 for interaction). The risk increase associated with high red meat consumption (OR, 10.68; 95% CI, 1.57-72.58) and the protective effect of high vegetable intake (OR, 0.07; 95% CI, 0.004-1.07) was also most pronounced among carriers of two long alleles (>/==" BORDER="0">19 CA). The length of the egfr CA SSR may increase the risk for familial breast cancers, and its effect could be modulated by dietary factors.