Circulating immune complexes have been detected in patients with inflammatory bowel disease (IBD). To determine if these complexes are related specificially to IBD or more generally to loss of intestinal mucosal integrity, we compared circulating immune complex levels in the sera of 86 IBD patients, nine pseudomembranous and nine bacterial colitis patients, and 42 healthy controls. Immune complexes were measured by a Raji cell radioimmunoassay. Raji detectable circulating immune complex levels were significantly higher in the IBD group than in the healthy controls (P<0.001). Circulating immune complex levels in the pseudomembranous-bacterial colitis group and the healthy controls were essentially identical. While nearly 20% of the IBD patients (16 of 86) had abnormally high levels, none of the patients with the other forms of intestinal inflammation (0 of 18) had abnormal levels. These data suggest that the circulating immune complexes present in inflammatory bowel disease patients are related to the IBD process rather than to non-specific mucosal cell (barrier) damage. Patients with intestinal inflammation and normal peripheral immune complex levels also had normal mesenteric vein levels. These data suggest that lack of formation, rather than more efficient hepatic reticuloendothelial clearance, was primarily responsible for the absence of detectable complexes in Raji negative individuals. Circulating immune complex levels did not correlate with type, location, severity, or extraintestinal manifestations of inflammatory bowel disease. The absence of Raji detectable circulating immune complexes in the majority of patients, even in those with extraintestinal manifestations, raises serious doubts about the pathogenic significance of such complexes. Nevertheless, as the circulating immune complexes appear to be disease related, they may be used to isolate and identify disease specific antigen(s) of possible aetiological importance.