OBJECTIVE The precise etiology of inflammatory bowel diseases (IBDs) is still unknown although dysregulation of apoptosis likely plays an important role in this pathogenesis. However, the significance of mucosal T-cell apoptosis in ulcerative colitis (UC) is unclear. In the present work we investigated the role of TNF-related apoptosis-inducing ligand (TRAIL), which is implicated in various human disorders. PATIENTS AND METHODS Results from a total of 393 UC patients and 1292 healthy individuals were analyzed in this study. We determined the three single nucleotide polymorphisms of TRAIL in 3' untranslated regions (UTR), and examined the plasma soluble TRAIL (sTRAIL) levels by enzyme-linked immunosorbent assay. RESULTS We found that the mutant genotypes of TRAIL (G1525A/G1588A/C1595T and G1525A and G1588A) were much lower in UC patients compared to the controls. Furthermore, mutant allele and genotype of TRAIL C1595T were more prevalent in severe UC patients than in other patients (p < 0.001; p = 0.005, respectively). The three polymorphic sites in 3'UTR were in a perfect linkage disequilibrium in our study. In contrast to controls, the GAT haplotype was increased (p < 0.001), while the AAT haplotype was decreased in UC patients (p < 0.001). Besides, the plasma levels of sTRAIL were significantly higher in UC patients than in controls (p < 0.001). CONCLUSIONS Our findings suggested that increased occurrence of the genetic mutations of TRAIL in 3'UTR and possibly decreased plasma levels of sTRAIL might lead to a lower risk of UC attack in Chinese patients.