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Aim: The genetic region of 6q25 containing the estrogen receptor-α (ER-α) gene is lost in a significant number of ovarian tumors. The aim of this study was to identify how inherited variation in the ER-α gene contributes to susceptibility to familial ovarian cancer. Methods: DNA obtained from 18 cases of familial ovarian cancer without mutation of the BRCA1 and BRCA2 genes, 20 cases with BRCA1 mutation, 20 cases of sporadic ovarian cancer, and 19 controls were screened for mutations in the coding region of the ER-α gene using direct sequencing. Results: Two germline missense variants at codons 307 [GCC(Ala)→TCC(Ser)] and 347 [ACC(Thr)→TCC(Ser)] were detected in two unrelated cases with BRCA1 mutation, but not in all other cases tested. Three polymorphisms in codon 10 [TCT→TCC(Ser)], codon 325 [CCC→CCG(Pro)], and codon 594 [ACA→ACG(Thr)] were identified in this series, and a higher frequency of the allele TCC at codon 10 and a lower frequency of the allele CCG at codon 325 were observed in familial cases without BRCA1 mutation, compared with those in familial cases with BRCA1 mutation, in both the sporadic cases and in the controls. Conclusions: We could not detect pathogenic mutations of the ER-α gene in ovarian cancer cases without BRCA1 mutation. However, association analyses of two polymorphisms suggest that the ER-α gene or a gene located close to the ER-α locus might be related to susceptibility of familial ovarian cancer without BRCA1 mutation. [ABSTRACT FROM AUTHOR]