Autoantibody responses to endometrial and serum antigens are a common feature of endometriosis. We have shown that the serum autoantibody response in endometriosis to a number of previously identified antigens, including alpha2-Heremans Schmidt glycoprotein and carbonic anhydrase, is specific for a carbohydrate epitope common to these proteins. Removal of carbohydrate moieties from these antigens resulted in a loss of antibody binding. Antibody reactivity was abolished following adsorption with the lectin jacalin, which specifically binds the Thomsen-Friedenreich (T) antigen (Gal beta1-3GalNAc). Demonstration that the autoantibodies also reacted with other Thomsen-Friedenreich antigen-bearing proteins, such as serum IgA1, hemopexin, and MMP-9, confirmed that this glycotope is involved in the autoantibody response. However, the autoantibody binding requires the presence of at least one sialic acid residue. Thus, the glycotope involved may be a sialylated T antigen. These findings allow us to hypothesize a number of mechanisms whereby the autoimmune response plays a direct role in several aspects of the disease process. The proposed mechanisms take into account the salient endocrine dependency of endometriotic lesions and other aspects of the disease process such as aberrant matrix metalloproteinase function and the ability of endometrial cells to implant at ectopic sites. The anti-T-like response may also be indicative of an underlying genetic defect in glycosylation or in the control of glycosylation by steroid sex hormones. Further characterization of this autoimmune response may prove useful in the development of serum-based diagnostic tests for endometriosis and may lead to the development of therapeutic strategies.