Interleukin-8 (IL-8), a CXC chemokine that recruits and activates inflammatory cells, plays a critical role in the pathogenesis of ulcerative colitis (UC). There are no studies on the association of single nucleotide polymorphisms (SNPs) of the IL-8 gene with the risk of UC. All 162 unrelated UC patients and 203 control subjects were analyzed for 5 IL-8 SNPs ((-845 (T/C), -738 (T/A), -353 (A/T), -251 (T/A) and +678 (T/C)) using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay and PCR-sequence-specific primers (SSP) method. Serum IL-8 concentrations were measured in all subjects. Individual SNPs were not associated with risk for UC. However, the frequency of -353A/-251A/+678T haplotype was significantly higher in UC patients than in healthy controls (OR=1.454, p=0.036). By subgroup analyses, this haplotype tended to be more common in severe UC patients than in those with mild-to-moderate disease (OR=2.281, p=0.027). Furthermore, patients with AAT diplotype showed significantly increased serum IL-8 concentrations than those with other diplotypes (p<0.001). These results suggest that IL-8 is a novel susceptibility gene to UC in Chinese UC patients, and furthermore, that IL-8 polymorphisms may be related to severe clinical subtype of UC.