In 153 patients with IBD, 64 with Crohn's disease (CD), and 89 with ulcerative colitis (UC), as well as in 54 healthy controls (HC), the frequencies of four known di-allelic polymorphisms in the genes for TNF-alpha and lymphotoxin alpha (LTalpha) were investigated. In the Dutch population, the alleles of these four polymorphisms are present in only five combinations, called TNF haplotypes: TNF-C, -E, -H, -I, -P. Furthermore, the relation with the presence of perinuclear anti-neutrophil cytoplasmic autoantibodies (P-ANCA) was studied. A small, but statistically significant, association between the polymorphism at position -308 in the promoter region of the TNF-alpha gene and UC was found. The frequency of the uncommon TNF-alpha -308 allele 2 was found to be decreased in patients with UC compared with HC (allele frequency of allele 2 in UC patients 0-15 versus 0.25 in HC, P=0.044). No significant differences in distribution of the TNF haplotypes were found between IBD patients and HC, although there was a tendency towards a higher frequency of the TNF-C haplotype in UC patients compared with controls (haplotype frequency 22% versus 13%; P=0.19). No statistically significant differences in distribution of the TNF haplotypes were observed between P-ANCA-positive and P-ANCA-negative UC patients. The strength of the associations indicates that TNF genes are not markers for the predisposition to suffer from IBD. They may, however, be markers of subsets of patients with UC and CD.