The administration of benzylpenicillin (penicillin) to man has been shown to induce the synthesis of antibodies of several distinct haptenic specificities and of several molecular classes (1-13). Specifically, skin-sensitizing antibodies of benzylpenicilloyl (BPO) haptenic specificity (1-7, 11) and of the minor determinant specificities (6, 7, 11) have been demonstrated. Also, BPO-specific antibodies of IgM and IgG classes have been identified in serum by passive hemagglutination (3-5, 8-10, 12, 13). We now report the results of assays for BPO-specific IgM, IgG, and skin-sensitizing antibodies, and minor determinant specific skin-sensitizing antibodies in various groups of patients with and without recent allergic reactions to penicillin. The data obtained describe the heterogeneous immune responses to penicillin made by human beings and permit initial inferences as to the nature of the immunological mechanisms that mediate allergic reactions to penicillin.'