Relationships between gender, age-of-onset of schizophrenia and reproductive age strongly suggest a key role for gonadal hormones, and more specifically for estrogens, in the etiology of the illness. Also, estrogens act as neural growth and trophic factors influencing neuron and glial cells in many areas of the central nervous system. Therefore, we investigated the association between schizophrenia and 4 genes related to estrogen metabolism. These genes are ESR1 (estrogen receptor 1), ESR2 (estrogen receptor 2), APOE (apolipoprotein E) and COMT (catechol-O-methyltransferase). The expression of APOE and COMT, which contain estrogen response elements, have been demonstrated to be regulated by the estrogen receptors. In this current association study, we examined 59 single nucleotide polymorphisms (SNPs) located in the ESR1 (26), ESR2 (14), APOE (7) and COMT (12) loci. Allele frequencies were evaluated in the schizophrenia (n=585)-control (n=615) sample and no association was found with any of the four genes. In conclusion, our data suggest that the four analyzed genes do not play an important role in susceptibility to schizophrenia.