The possibility that the neutrophil autoantibodies associated with ulcerative colitis represent a genetic marker of susceptibility was investigated by determining their prevalence in unaffected relatives of patients. Neutrophil autoantibodies were detected using an enzyme-linked immunosorbent assay, and positive values were confirmed by indirect immunofluorescence. An increased prevalence of neutrophil antibodies was found not only in the probands (68%, 26/38) but also in their clinically unaffected family members (15.7%, 17/108) compared with controls (2.9%, 1/35) (P less than 0.0001 and P less than 0.05, respectively). These results were confirmed with sera from a second center, where 86.4% (19/22) of probands were positive and 20.9% (9/43) of their relatives were positive. The prevalence of neutrophil autoantibodies in the relatives of probands who were antibody positive (21.4%) was significantly greater than the prevalence in relatives of probands who were antibody negative (7%; P less than 0.05). The findings are consistent with these antibodies being a potential marker of genetic susceptibility to ulcerative colitis and suggest the possibility of genetic heterogeneity within this disease.