Estrogens represent risk factors for endocrine-related cancers and play also an important role in the development and progression of other malignancies. In order to analyze the associations between estrogen receptor gene alpha polymorphisms and cancers susceptibility, we genotyped six single nucleotide polymorphisms (SNPs) in 163 Caucasian cancer patients--103 breast cancers and 60 other malignancies (colorectal, bladder, hepatocellular carcinoma and acute myeloid leukemia)--and 114 healthy controls using hybridization probes. We performed Armitage`s association trend-test to evaluate the risk. Linkage disequilibrium (LD) was assessed for each pair of markers. The genotypes CC and CT of rs3798577 were significantly associated with the cancers risk (p-trend breast = 4 × 10(-5); p-trend cancers = 1 × 10(-5)); in discrepancy with breast cancer where the C-allele represented the risk allele, for bladder, hepatocellular carcinomas and leukemia, the T allele seems to confer susceptibility. The minor G allele of rs1801132 was protective in our cases (p = 1 × 10(-4)); for rs2228480, the heterozygous frequency was higher for cancer groups (p = 0.03); the SNP pairs rs2228480&rs3798577 and rs2234693&rs9340799 were in low LD; the haplotypes T-A of rs2234693&rs9340799 and G-C of rs2228480&rs3798577 showed a trend to be higher represented in breast cancers; T allele of rs2234693 was higher expressed in breast, colon cancers and leukemia; rs2077647 was associated with colon (p = 0.008, C-risk allele) and bladder (p = 0.01, T-risk allele) cancers. We concluded that ESR1 polymorphisms may have distinct impact in carcinogenesis and further genotyping will establish whether these findings remain significant in larger cohorts.