BACKGROUND IgE and IgG antibodies to penicillins can have different specificities. However, this response, including the recognition of the different parts of penicillin, has never been studied in the same subject. OBJECTIVE Study of the specificity of IgE and IgG antibodies and the relevant parts of the penicillin molecule that contribute to the hapten binding site in sera from human. METHODS Specific IgE antibodies were determined by RAST and specific IgG antibodies by ELISA. The recognition of the different molecules was studied by inhibition studies. RESULTS Seven sera with IgG and IgE antibodies to amoxicillin and benzyl penicillin were analyzed. IgE antibodies recognized mainly two different epitopes: in one, the side chain was a relevant part of the epitope, in the other, it was the nuclear portion. IgG antibodies recognized the nuclear portion in all instances. In the same subject, antibodies of different isotype and specificity were found. CONCLUSIONS Subjects who develop simultaneously IgE and IgG antibodies to penicillins show different specificities. This proves that different populations of antibodies recognize different epitopes.