Glutathione disappears as a soluble, nonprotein component after it has been added to serum, either in the reduced (GSH) or oxidized (GSSG) form. When GSH is added to serum it is rapidly oxidized to GSSG by some dialyzable component of serum. Glutathione is lost because of interaction of serum proteins with the GSSG formed in this manner or added directly. A similarly rapid loss of glutathione occurs in the presence of hemoglobin only if acetylphenylhydrazine is also present. This loss of glutathione in the presence of a redox drug is the result of a direct interaction between GSH and hemoglobin, in contrast to the reaction occurring in serum. The implications of these findings for hematologic disease are discussed.