OBJECTIVE Prostate cancer is a very common hormone-related malignancy in Western countries. It is initially dependent on androgen stimulation but in vitro growth of prostate cancer cells are also dependent on estrogen. Our goal was to elucidate if some polymorphisms of estrogen receptor alpha gene might be associated with the risk of prostate cancer. METHODS Using DHPLC techniques, each coding exon of the estrogen receptor alpha gene was screened for new polymorphisms in germline DNA from 96 healthy controls and 96 sporadic prostate cancer cases. Identified polymorphisms were then genotyped and their distribution compared between the two populations. RESULTS Thirteen polymorphisms were identified. A difference was found in the distribution of one newly identified polymorphism, namely a GGGA repeat located in the first intron of the gene. The common wild type genotype consisted of two alleles with five GGGA repetitions (5/5 genotype). Indeed this 5/5 genotype was found in 294/296 controls (99.3%) and 285/294 patients (96.9%; OR, 4.6; 95% CI, 0.99-21.67). Among the nine patients with a different genotype, one was 4/5, seven were 5/6 and one was 6/6. CONCLUSIONS These results suggest that variants of the GGGA polymorphism from the estrogen receptor alpha gene may be associated with an increased risk of developing prostate cancer.