Abnormal innate immune responses toward luminal bacteria play an important role in the pathogenesis of inflammatory bowel disease.It has been demonstrated that bacteria having CpG DNA ameliorate experimental colitis in mice,and Toll-like receptor 9 (TLR9) signaling mediates the anti-inflammatory effects in mouse colonic inflammation.A gene variation in NOD2/CARD15 has been reported in Crohn’s disease (CD) patients in Western countries,but this variation has not been identified in Japanese CD patients.Therefore,we hypothesized that TLR9 is a key factor in the development of ulcerative colitis (UC),and we investigated gene mutations and polymorphisms of TLR9 in Japanese UC patients.Three single nucleotide polymorphisms (SNPs) in TLR9 were identified in healthy controls,and were assessed in 48 UC patients and 47 healthy controls.Control subjects were matched for age,sex and date of blood sampling from among a subgroup of participants.We found that TLR9-1486CC,1174GG and 2848AA increase the risk of UC [odds ratio (OR) 2.64,95% confidence interval (95% CI):1.73-6.53,P=0.042],and TLR9-1486TT,1174AA and 2848GG decrease the risk of UC (OR 0.30,95% CI:0.10-0.94,P=0.039),although there were no correlations between SNPs and disease phenotype or TLR9 mRNA expression.These findings suggest that TLR9 polymorphisms are associated with increased susceptibility to UC. Abnormal innate immune responses toward luminal bacteria play an important role in the pathogenesis of inflammatory bowel disease. It has been characterized that bacteria have CpG DNA ameliorate experimental colitis in mice, and Toll-like receptor 9 (TLR9) signaling mediates the anti-inflammatory effects in mouse colonic inflammation. A gene variation in NOD2 / CARD15 has been reported in Crohn’s disease (CD) patients in Western countries, but this variation has not been identified in Japanese CD patients. Before, we hypothesized that TLR9 is a key factor in the development of ulcerative colitis (UC), and we investigated gene mutations and polymorphisms of TLR9 in Japanese UC patients. Single single nucleotide polymorphisms (SNPs) in TLR9 were identified in healthy controls, and were were in 48 UC patients and 47 healthy controls. Control subjects were matched for age, sex and date of blood sampling from among a subgroup of participants. We found that TLR9-1486CC, 1174GG and 2848AA increase th e risk of UC [odds ratio (OR) 2.64, 95% confidence interval (95% CI): 1.73-6.53, P = 0.042], and TLR9-1486TT, 1174AA and 2848GG decrease the risk of UC (OR 0.30, 95% CI: 0.10-0.94, P = 0.039), although there was no correlations between SNPs and disease phenotype or TLR9 mRNA expression. These findings suggest that TLR9 polymorphisms are associated with increased susceptibility to UC.