Since only scarce data are available on the immune response against heat shock proteins (HSP) in inflammatory bowel disease (IBD), we have measured with an ELISA method serum levels of IgG, IgA, and IgM antibodies to mycobacterial HSP65 and human HSP60 in 66 patients with Crohn's disease (CD), 42 patients with ulceratiVe colitis (UC), and 126 age-and gender-matched healthy controls. Serum concentration [median (25th-75th percentiles) of IgG anti-HSP65 antibodies was substantially lower in patients with either CD (P < 0.01) or UC (P < 0.001) than in healthy controls, while no difference was found in the levels of anti-HSP60 antibodies. Low anti-HSP65 antibody levels were measured in patients with active CD and in both active and inactive UC, and only in IBD patients with no extraintestinal manifestations. In conclusion, our present findings indicate that an abnormal immune response to bacterial HSP65 or some epitopes of the protein may contribute to the dysregulation of host defenses against certain intestinal bacteria.