Recent reports suggested that lipocalin-type prostaglandin D synthase (L-PGDS) is implicated in atherogenesis. In the present study, we investigated the polymorphism of the L-PGDS gene and examined its relationship with the severity of carotid atherosclerosis which is determined as the maximum intima-media thickness in the common carotid artery (C-IMT(max)). We identified 6 single nucleotide polymorphisms (SNPs) of the L-PGDS gene in Japanese. A rare SNP with an amino acid change (1535C>G in exon 4, Leu79Val) and a common SNP (4111 A>C in 3'-untranslated region) were selected for genotyping in 782 Japanese hypertensive subjects. There was no significant difference among genotypes in 1535C>G, however, in 4111 A>C, serum levels of high-density lipoprotein (HDL) cholesterol were significantly higher in subjects with A/A genotype than those with A/C and C/C genotypes. C-IMT(max) was significantly smaller in subjects with A/A genotype than those with A/C and C/C. Logistic regression analysis revealed that the presence of A/A genotype significantly reduced the risk for increased C-IMT(max), even after adjustment for other known risk factors [adjusted odds ratio: 0.71 (95% CI: 0.58-0.88)]. Our results suggested that 4111 A>C polymorphism in the L-PGDS gene contributes to the development of carotid atherosclerosis in Japanese hypertensive patients.