Young rats were subjected to a dietary leucine overload for several weeks. Although no significant changes in growth, food consumption, and hematological and immune responsiveness occurred when the basic diet was balanced (18% casein), rats which were both overloaded with leucine and subjected to a protein-poor diet (4% casein) displayed a strong impairment of immunological reactions to sheep red cells (rosette and plaque-forming cells in the spleen, serum hemagglutinins, and hemolysins). The effect was significantly more pronounced than in rats on a protein-poor nonsupplemented diet or in pair-fed controls on a balanced diet. The immunodepression was as profound as after complete protein deprivation. It is suggested that a secondary defect in valine and isoleucine utilization may play a role in the harmful effects of excess leucine, because isoleucine and especially valine have been shown to be highly deleterious to lymphopoiesis.