Angiogenesis is an important step in the development of cancer. Vascular endothelial growth factor is a major regulator of breast cancer angiogenesis, the effects of which are transmitted through the kinase domain receptor (KDR). Up-regulation of KDR by periostin (POSTN) induces angiogenesis. We screened the KDR and the POSTN genes for published single nucleotide polymorphisms (SNPs) and chose two SNPs in each gene for further analyses. We carried out a case-control study consisting of 412 familial and 912 unselected breast cancer cases together with ethnically and geographically selected controls. Genotype, haplotype and genotype combination analyses were carried out to evaluate their effect on susceptibility to and prognosis of breast cancer. A haplotype in the POSTN gene was associated with an increased risk even after correction for multiple comparisons. Nominal associations between the SNPs and prognostic indicators were also observed. Tumors of the KDR 472His allele carriers were less often progesterone receptor negative according to both genotype and haplotype analyses (OR 0.61, 95%CI 0.40-0.92 and OR 0.60, 95%CI 0.40-0.91, respectively). The POSTN -33G allele carriers had more often high grade and estrogen receptor negative tumors (OR 1.75, 95%CI 1.02-3.01 and OR 1.70, 95%CI 1.04-2.78, respectively). The overall and cancer specific survival after 15 years of follow-up was more than 75%, and it did not depend on the genotype. Although a major effect of the SNPs in the KDR and the POSTN genes on breast cancer susceptibility and prognosis was excluded, the effect of the POSTN C-33G SNP on prognosis needs further characterization.