The PHA response of spleen cells from mice immunized with heterologous γ-globulin, serum albumin or erythrocytes 1 to 2 days previously may be severely impaired. The impairment disappears within a week. Inclusion of the specific antigen in culture can cause further suppression or unresponsiveness. The suppression of the PHA response was increased by increasing the immunizing dose of antigen, the amount of antigen in culture, the amount of PHA used for stimulation, the number of cells in culture, the use of an adjuvant in immunization, and the use of more stimulatory sera in culture. The PHA response of spleen cells from mice given a tolerogenic form of bovine γ-globulin (BGG) was suppressed in the presence of BGG, although less so than that of mice given an immunogenic form of the antigen. The tolerogenic form was, however, more suppressive when added to the culture. The ability of a relatively small number of antigen reactive cells to markedly affect the PHA response suggests that suppressive cell interactions play an important causative role.