In Lewy body disease, inflammation is discussed to be involved in the pathophysiological cascade. Osteopontin (OPN) is a multifunctional molecule, which is increased in inflammatory states. Here, we analyzed the allele frequency of two SNPs of the OPN gene, serum, and CSF OPN levels in Lewy body disease patients and controls. In accordance with our previous findings, we detected increased serum (P = 0.006) and CSF OPN levels (P = 0.0003) in the Lewy body disease cohort, compared to non-Lewy body disease subjects. The genotypic variation of SNP-66 was associated with the occurrence of Lewy body disease (odds ratio: 2.64, 95% CI 1.07-6.54, unadjusted P = 0.036). SNP+1239 was not related to Lewy body disease prevalence (odds ratio 1.61, 95% CI 0.66-3.91, P = 0.29). Genotype prevalence and OPN levels were not significantly related. These findings suggest that OPN is associated with the occurrence of Lewy body disease and SNP-66 may be a susceptibility factor.