Three polymorphisms in the human tumor suppressor gene p53 (BstUI and MspI RFLPs in exon 4 and intron 6 respectively and a 16 bp duplication in intron 3) and their haplotype combinations were studied in patients with breast cancer and controls. A significant increase in the codon 72 BstUI A1 (pro) allele frequency (P = 0.016) and of individuals carrying the pro allele (pro/pro and pro/arg) (OR, 1.47; P = 0.01 4; 95 % CI, 1.08-2.00) was observed in breast cancer. This increase was most pronounced in highly differentiated breast cancer. Significant associations were found only in BstUI and haplotypes containing this polymorphism, which indicates that the codon 72 pro allele may be functionally involved in low malignancy breast cancer. The distributions of genotypic combinations in breast cancer patients and controls were significantly different (P = 0.005). Two BstUI-16 bp-MspI combinations were significantly overrepresented; 2-1, 1-1, 2-2 (OR, 1.61; 95% CI, 1.13-2.30) and 1-1, 2-1, 2-1 (OR, 2.94; 95% CI, 1.37-6.27).