Nonspecific IgE binding to allergens was observed in testing myeloma IgEs, namely, IgE-VL and IgE-PS, chimeric IgE (IgE-JW8), and the recombinant IgE Fc epsilon peptide CH1-CH4, in two different immunoassays. This binding was concentration-dependent but detectable only at higher IgE concentration. In RAST inhibition, IgE-allergen interactions could be reduced by using either matching or nonmatching allergens. In order to test whether the nonspecific binding of IgE to allergens was due to carbohydrate interaction, myeloma IgEs and the chimeric IgE were desialized with neuraminidase. Desialized samples were equally well recognized by xenogenic antibodies as native IgEs, but binding of IgE to Fc epsilon receptors on basophils was affected by the treatment, as shown in the histamine-release assay. Desialization of IgE affected also its binding capacity to allergens in RAST: binding of chimeric IgE was reduced, but nonspecific binding of myeloma IgE-VL was enhanced. Hence, nonspecific allergen-IgE binding may be partly due to a lectin-like interaction, but may depend mostly on the tertiary structure of IgE. Thus, nonspecific IgE-allergen interactions might present a problem 1) at high IgE concentration, and 2) depend on the grade of sialization of IgE, which might affect its conformation. This may explain why patients with elevated total IgE levels often have multiple weak positive RASTs with non-cross-reactive allergens.