According to incidence data from Italian cancer registers, colorectal cancer is the third most common cancer in both men and women even considering skin non-melanoma cancers, lung and breast cancers. Moreover it represents the third absolute leading cause of cancer death in women and the fourth in men. Although data on Italian population regarding the role of estrogens in colorectal cancer have not yet been collected, several strands of evidence from international epidemiologic datasets indicate their protective role against the development of colon cancer. The effect of estrogens are mediated by oestrogen receptor (ERs), ERα and ERβ but ERβ has been identified as the predominant ER subtype in human colon, been expressed at higher levels in normal mucosa and significantly decreasing along tumour progression. According to the existence of a genetic predisposition to sporadic colorectal cancer, which is based on the carriage of common, low-penetrance polymorphic alleles, including those of PPARγ, NAT and VDR genes, polymorphism analysis of colorectal cancer has been recently attempted but none of the studies took into consideration the analysis of ERβ polymorphisms, dealing only with the most common estrogen receptor. On the basis of experimental and epidemiological data reported in the literature we thought that polymorphisms of ERβ had to be considered, as well as those of ERα, and indeed we performed an association study on 166 subjects affected by sporadic colorectal cancer and 197 healthy controls matched for age and sex. All enrolled subjects signed the informed consent. No association was ascertained between nor ERα PvuII or XbaI polymorphisms, while a significant association emerged between ERβ AluI genotype and colorectal cancer. In particular homozygous AA genotype was associated with a reduced risk (RR 0.57, P<0.005) and the homozygous opposite genotype aa with a higher risk (RR 1.59, P<0.05) for sporadic colorectal cancer. No further association was detected between ERα or ERβ genotypes and tumour features like Dukes staging, and histopathology.