Genetic factors have a definitive role in the etiology of ulcerative colitis (UC). The mode of inheritance suggests a polygenic disease with the penetrance of the genetic factors being strongly influenced by environmental factors. Several studies have been reported associations between UC and the polymorphism of genes that are located in the major histocompatibility complex (MHC) on the short arm of chromosome 6. The human leukocyte antigen (HLA) class II genes are candidates for a role in the pathogenesis of UC, because their products play a central role in the immune response. The MHC region contains numerous immune related genes, and it has now become clear that different alleles of the MHC genes are strongly linked. Association studies have suggested a role for HLA-DR alleles in disease susceptibility to UC. Thus, HLA-DRB1*0103, DRB1*1502 and DRB1*12 were found to be positively associated with UC. On the other hand, the tumor necrosis factor alpha (TNF-alpha) gene encodes a proinflammatory cytokine that is found in increased concentrations in the mucosa of patients with inflammatory bowel disease. The regulation of TNF expression is in part genetically determined because the polymorphisms -238, -308, -863, -857, and -1031 found in the promoter region are associated with increased TNF production. Recent data suggests that TNF polymorphism may be more important in determining susceptibility to UC and these TNF markers could predict response to infusion with chimeric anti-TNF antibody.