We investigated the possibility that subjects with IgE antibodies to an inhalant insect allergen, such as caddis fly, might also have antibodies to cross-reacting carbohydrate determinants (CCDs). IgE antibodies to cross-reacting allergens in caddis flies, mussels, oysters, shrimps, crabs, honeybee, and yellow jacket venoms were determined by RAST, RAST inhibition, and immunoblot studies with sera from three different sources: (1) sera of patients with well-defined inhalant atopy to caddis fly, (2) sera with IgE anti-CCD antibodies from subjects without known exposure to caddis fly, and (3) hyperimmune antisera with IgG anti-CCD antibodies raised as a result of immunization of rabbits with grass-pollen extract, buckwheat glycoprotein, or with honeybee venom. Sera from groups 2 and 3 reacted with Sepharose-coupled caddis fly extract in a RAST-type assay and elicited virtually identical patterns on immunoblots of caddis fly extract separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis, whereas the sera from group 1 atopic patients did not react with CCD-rich material. However, indications for other types of cross-reacting antibodies were detected. The IgE antibodies of one of the patients studied (who was allergic not only to caddis fly but also to shellfish) were found to detect a cross-reacting homologous protein in extracts of mussel, oyster, shrimp, crab, honeybee, and yellow jacket venom. Preliminary results suggest that this cross-reacting 13 kd protein, the most prominent caddis fly allergen, is an invertebrate hemoglobin (erythrocruorin)-like molecule. These studies suggest the possibility that patients sensitized by exposure to caddis fly antigens could develop allergic reactions during their first exposure to shellfish or to their first bee sting.