Summary: Reduction of anti-ragweed γE antibodies in 0.1 M mercaptoethanol for 1 hr followed by alkylation with iodoacetamide resulted in a great decrease of their skin-sensitizing activity, whereas treatment of the antibodies with 0.01 M mercaptoethanol did not have a significant effect. The γE antigenic determinants in the molecules were not impaired by reduction with 0.1 M mercaptoethanol and alkylation. The antigen-binding activity of the antibodies was diminished to about one-third by the treatment. It was also found that the affinity of γE molecules for skin tissues was lessened by the treatment. On a weight basis, the ability of γE to block passive sensitization with reaginic antibodies of a heterologous antigen system was diminished to one-fifth by the treatment. Passive sensitization with the reduced-alkylated γE antibodies did not persist for a long time. The results indicated that the effect of reduction-alkylation on the γE antibodies involve both antibody-combining sites and tissue fixation sites in the molecules. The structural basis of the affinity of γE molecules to target cells was discussed.