Introduction: The biological significance of sequence variants in form of SNPs needs to be carefully evaluated, as conflicting associations with cancer predisposition have been reported. Haplotypes, the combination of closely linked alleles on a chromosome, play key roles in the study of the genetic basis of disease. There is strong evidence that different polymorphisms within a single gene in cis position can interact to create a large effect on the observed phenotype. Several polymorphisms have been reported in the p53 gene. Some of these are within the coding region and may affect the function of the p53 protein, others are within introns or non-coding regions, and their significance is unclear. In this study, we investigated the association of specific p53 genotypes and haplotypes with risk of breast cancer. Methods: One hundred and fifteen patients with breast cancer and 63 healthy individuals were analyzed. DNA was isolated by salting out. The polymorphic sites were analyzed by PCR RFLP. Pearson's chi(2) and Kolmogorof Simirnow tests were used for statistical analyses. Extended haplotype frequencies were estimated. Results: The distribution of the genotypes was similar for all three polymorphisms in the cases and the controls. Our estimated haplotype results indicate that the intron 3 (+16 bp) vertical bar exon 4 (Arg) diplotype and the intron 3 (+16 bp) I exon 4 (Arg) I intron 6 (G) haplotype combinations are overrepresented in the breast cancer group, suggesting that the intron 3 (+16 bp) I exon 4 (Arg) alleles may play a role in breast carcinogenesis. Conclusion: We conclude that two haplotypes harboring the intron 3 polymorphic (+16 bp) allele are associated with a higher risk of breast cancer in the Turkish population. (C) 2007 International Society for Preventive Oncology. Published by Elsevier Ltd. All rights reserved.