Summary: The effects of rabbit antilymphocyte (ALS) and antithymocyte (ATS) sera on the early primary and secondary response of mice to sheep RBC were studied using the hemolytic plaque technique as an assay system for enumerating antibody-producing cells. Immunosuppressive effectiveness was related to the routes of immunization and serum treatment. Intraperitoneal administration of ALS or ATS was the most effective in reducing the number of splenic plaque-forming cells (PFC), and intravenous administration was the least effective when associated with i.p. immunization. Mice treated successively on days -1, 0 and +1 with 0.25 ml of ALS or ATS had a peak response of 4000 PFC by 76 hr following primary immunization compared to 387,000 for nontreated controls at 96 hr. There was a prolongation of the lag phase and a truncation of the exponential phase which may have been due to a reduction in the number of stimulated antigen sensitive precursor cells. Mice treated with ALS or ATS at the time of primary immunization had a reduction in both unfacilitated and facilitated splenic PFC 3 days following a second injection of SRBC. Serum hemagglutinin and hemolysin titers were identical to controls, and it was suggested that peritoneal lymph nodes may have compensated for the decreased splenic response. Infusion of ALS-treated and immunized mice with 50 × 106 spleen cells from normal syngeneic donors resulted in some restoration of immunocompetence both in terms of splenic PFC and serum antibodies.