Reelin, a serine protease encoded by the RELN gene, is part of the apolipoprotein E (apoE) biochemical pathway that is involved in the pathogenesis of Alzheimer's disease (AD). Sex-related differences in the epidemiology, pathology and clinical characteristics of AD have been reported. To explore the potential contribution of RELN gene variants in the pathogenesis of AD, we investigated three polymorphisms spanning the RELN locus, i.e., a triplet tandem repeat in the 5'UTR and two single-nucleotide polymorphisms (SNPs) rs607755 and rs2229874, located in the splice-junction of exon 6 and in the coding region of exon 50. The analysis was made in 223 sporadic AD patients and 181 age-matched controls of Caucasian ethnicity. Significant differences between AD patients and controls were found in distribution of 5'UTR and rs607755 genotypes, whereas no differences were found in the distribution of rs2229874 genotypes. When patients and controls were divided according to sex, significant differences in genotype distribution were found in females and not in males, also after adjustment for APOE genotypes. These findings suggest that RELN gene variants may play a role in the pathogenesis of AD, particularly in females.