An antigen-specific suppressive factor was extracted from spleen cells of mice made tolerant by injection of deaggregated human γ-globulin (HGG). The active material could be prepared from T cells, obtained by passaging spleen cells through an anti-immunoglobulin column, although not from cells adherent to the column nor from spleen cells pretreated with anti-Thy-1 serum and C. This factor was antigen-specific since it was retained on immunoadsorbents containing HGG, but not on columns coated with antibody to HGG or with irrelevant antigens. Despite its specificity for antigen it did not bear any classical immunoglobulin determinants. Its m.w. ranged between 30,000 and 55,000 daltons. It was a product of the I region of the major histocompatibility complex since it carried Ia determinants. The properties of this factor are very similar to those reported elsewhere for suppressive factors obtained from primed T cells, cells from nonresponder mice, and allotypespecific cells. This suggests the existence of a major class of immunoregulatory molecules, nonimmunoglobulin in nature, and responsible for the mediation of antigen-specific T cell-dependent suppression.