AbstractWith an incidence of about 300 000 new cases colorectal cancer (CRC) is the second leading cause of cancer‐related death in Europe and the United States. Environmental and genetic factors influence CRC risk. Hypoxia‐inducible factor‐1 (HIF‐1), a heterodimeric protein composed of two subunits, HIF‐1 alpha and HIF‐1 beta, plays a critical role in oxygen homeostasis and is involved in angiogenesis and cell proliferation. The gene for the HIF‐1 alpha subunit (HIF1A) carries two common missense mutations—P582S (rs11549465) and A588T (rs11549467)—which both have been related to increased trans‐activation capacity of HIF1A. In our case–control study we investigated the association between these polymorphisms and CRC risk. We investigated 381 patients with histologically confirmed CRC and 2156 control subjects. HIF1A genotypes were determined by exonuclease (TaqMan) assays. For determination of microvessel density (MVD) tumor sections were stained using a mouse monoclonal antibody recognizing the pan‐endothelial marker CD31. In a multivariate logistic regression analysis including age and sex neither the HIF1A 582S allele (Odds ratio: 1.204; 95% confidence interval 0.911–1.592; P = 0.193) nor the 588T allele was significantly associated with CRC (Odds ratio: 0.851; 95% confidence interval 0.444–1.631; P = 0.626). However, in an exploratory analysis, the HIF1A 588T allele was associated with tumor localization (P = 0.016) and tumor size (P = 0.003). MVD was similar in tumors of patients carrying HIF1A 588T allele and patients without this rare allele. We conclude that functional polymorphisms in the HIF1A gene do not modify CRC risk but maybe associated with clinic‐pathological features of the disease. © 2010 Wiley‐Liss, Inc.