Summary: Treatment of adult rats with bovine γ-globulin induced specific unresponsiveness to a later challenge with antigen and adjuvant. Various parameters of the immune response were inhibited to varying degree, among them the development of Arthus and delayed skin reactivity, formation of hemagglutinating and precipitating antibody, and immune clearance. Nonaggregated antigen was found to be more effective than the aggregated form in the induction of unresponsiveness. Doses as low as 0.02 mg induced significant depression of certain responses, Arthus reactivity in particular, and maximal inhibition followed doses of 2.0 mg. No zone effect was observed, comparable to that reported in mice. A maximal effect was observed when pretreatment was given 4 or 12 days prior to challenge; unresponsiveness decreased progressively at longer intervals (35 or 70 days). Intravenous antigen administered simultaneously with or 4 days after the challenge reduced the subsequent response to a moderate extent. The pretreatment itself elicited formation of circulating antibody but was nonetheless effective in inducing unresponsiveness. Irradiated recipients of spleen cells from pretreated donors showed a transient inability to react following a standard challenge. Repeated injection of zymosan (accompanied by enhanced reticuloendothelial activity) enhanced antibody formation induced by injection of antigen intravenously and prevented partially its ability to suppress the response to later challenge.