Nonspecifically aggregated E myeloma protein induced erythema-wheal reactions in human and monkey skin but not in guinea pig skin. The minimum doses of the aggregated γE required to induce the reactions in the normal human and monkey skin were 1 ng N and 10 ng N, respectively. Monomer protein did not give such a skin reaction in any of the three animal species. Evidence was presented that combination of the aggregated γE with target cells, to which reaginic antibodies attach upon sensitization, is essential for induction of the skin reactions in the primates. Aggregated γG induced erythema-wheal reactions in all of the three animal species studied, but the minimal reactive dose of the aggregated γG was 200 to 500 times more than the dose of aggregated γE. E myeloma proteins sensitized monkey but not guinea pig skin for reversed type passive cutaneous anaphylaxis. In contrast, normal γG that had skin-sensitizing activity in the guinea pig failed to sensitize monkey skin. Aggregated γE, which had skin reactivity in the primates, did not fix complement. Lack of complement fixation by the aggregated γE was confirmed by C1a and C3 fixation tests. Failure of aggregated γE to fix complement indicated that neither complement nor anaphylatoxin was involved in the mechanisms of reaginic hypersensitivity reaction by γE systems.