Development of Alzheimer's disease (AD) is characterized by progressive neuronal death and a decline in learning and memory. Mutations in human senataxin (SETX), an ortholog yeast protein of Sen1, have been identified to cause the syndrome of ataxia with oculomotor apraxia type 2 (AOA2) and juvenile amyotrophic lateral sclerosis (ALS4), two types of progressive motor neuron degeneration. However, the relationship between the SETX gene, which is involved in the regulation of RNA processing and DNA repair, and the predisposition for AD remains unclear. In this research, potential association of polymorphisms in the SETX gene with AD was investigated. A case-control study of a Chinese Han population in Taiwan was performed. Three single-nucleotide polymorphisms (SNPs), 3455T>G (rs3739922), 3576T>G (rs1185193) and 7759A>G (rs1056899) were studied. The experimental data showed that upon genotyping of the exonic polymorphism in the SETX gene, the T allele appeared at a lower rate than the G allele at position 3455 in AD patients compared with normal groups (P < 0.05, odds ratio (OR), 0.59, 95% confidence interval (CI), 0.40-0.89). Subjects with the GA genotype at position 7759 have higher incidences of AD development than with the AA genotype (P < 0.05, OR, 6.45, 95% CI, 1.24 to 33.70). Our results also showed that with six haplotypes (Hts) observed from the analyzed polymorphisms, distributions of the Ht4-GAA and Ht5-GCA haplotypes appeared to be significant 'risk' haplotypes between AD patients and controls (both P < 0.05, OR, 8.44, 95% CI, 1.07-66.60). These observations suggest that genetic variations in the SETX gene may contribute to AD pathogenesis in the Taiwanese Han population.