SDS polyacrylamide gel electrophoresis separates desmosomal proteins and glycoproteins of bovine tongue epithelium by their relative molecular mass. The Western immunoblot technique was used to reveal the reactions of desmosomal proteins and glycoproteins with naturally occurring antibodies in serum and gingival crevicular fluid (GCF). Naturally-occurring serum and GCF antibodies (IgG and IgM) from periodontitis patients and healthy, unaffected controls reacted with desmosomal proteins (desmoplakins) and glycoproteins (desmogleins). Sera from 90% of subjects with periodontitis showed increased reactions of IgG with desmoplakins (240 and 210 kDa) and 80% with desmogleins (165, 130, and 115 kDa), when compared with unaffected controls. Patients' IgG reacted with desmosomal components more strongly than IgM. IgG antibodies against desmosomal antigens in GCF showed similar specificities from patients and healthy subjects and to their serums. When GCF within individuals with periodontitis was compared, anti-desmosomal IgG from diseased sites showed greater reactivity than healthy controls. These data suggest that anti-desmosomal antibodies are a normal part of the immune repertoire. The presence of elevated titers of anti-desmosomal antibodies appear to distinguish periodontitis from unaffected sites. When detected, elevated titers of anti-desmosomal antibodies may contribute to the pathogenesis and indicate increased risk of periodontitis.