We examined patients of Han nationality diagnosed with irritable bowel syndrome with diarrhea (IBS-D) in Guangdong, China, to analyze the correlation between DQB1 allele polymorphisms and the genetic susceptibility to IBS-D. A total of 120 IBS-D patients of Han nationality in Guangdong, China, and 60 healthy control volunteers were included. DQB1 allele polymorphisms were investigated by polymerase chain reaction. Subjects’ serum interleukin (IL)-10 level, colonic permeability, and tight junction marker zonula occludens 1 (ZO1) mRNA level were also investigated. Our data showed that the DQB1*02 allele frequency was significantly higher in IBS-D patients, while the DQB1*0603 frequency was lower than in healthy volunteers. The DQB1*03, DQB1*04, DQB1*05, DQB1*0601, DQB1*0602, and DQB1*0604 alleles did not show significant differences between IBS-D patients and healthy controls. Furthermore, patients with DQB1*03- positive and DQB1*0603-negative alleles showed more severe colonic permeability and lower serum IL-10 level and ZO1 level compared to healthy controls or even IBS-D patients with other genotypes. The present study indicated the DQB1*02 or DQB1*0603 alleles are related to IBS-D occurrence in Guangdong, China, and the mechanism of the disease may be related to reduced serum IL-10 levels. © FUNPEC-RP.