Results of genetic association studies in UC are conflicting. We propose that the power of candidate gene studies will increase when disease heterogeneity is taken into account. Phenotype frequencies of molecularly defined HLA-DR alleles, polymorphisms in the tumour necrosis factor-alpha (TNF-alpha), lymphotoxin-alpha (LT-alpha), IL-1 receptor antagonist (IL-1Ra) and IL-1beta genes were determined in 98 clinically well characterized UC patients with a mean period of follow up of 10 years, and ethnically matched healthy controls (HC). The alleles HLA-DRB1*0103 (phenotype frequency 6% versus 0.2%; P = 0.0002; odds ratio (OR) 27.6) and DRB1*15 (41% versus 26%; P = 0. 001; OR = 2.0, compared with HC) were associated with overall disease susceptibility. Subgroup analysis revealed that DRB1*15 was only increased in females (53% versus 24%; P < 0.0001; OR = 3.5), but not in males. With regard to disease localization, all DRB1*0103+ patients had extensive disease (P < 0.002; OR = 33.5), and DRB1*15 was found in 59% of females with extensive colitis (P < 0.0001; OR = 4.4). DRB1*0103 was significantly increased in patients undergoing colectomy (P < 0.0002; OR = 84). No association between overall disease susceptibility and the cytokine gene polymorphisms were found. Subgroup analysis revealed several significant associations, but most did not retain significance when corrected for multiple comparisons. However, a noticeable finding was that haplotype TNF-C was significantly associated with progression in extent of disease (P = 0.003, OR = 20.4). This study provides additional evidence for the role of DRB1 alleles in the susceptibility to UC, and supports the hypothesis that these alleles may determine the severity of the disease. The cytokine gene polymorphisms evaluated in this study do not seem to be strong risk factors for the overall disease susceptibility in UC, but may be involved in determining the severity of the disease.