Antigen-specific tolerance of T cells to minor lymphocyte stimulatory (Mls) antigens can be induced in mice by neonatal injection of foreign lymphohematopoietic cells. Although immune responses to Mls^a antigens are controlled by B cells, CD8⁺ T cells were the most effective cell type for induction of Mls^a tolerance. Tolerance was evident in both thymus and lymph nodes and could be induced by as few as 2 × 10⁴ CD8⁺ T cells; these cells were 50 to 100 times as potent as CD4⁺ cells or B cells in causing functional tolerance and deletion of V_β6⁺ T cells. Thus, intrathymic contact with antigens expressed on CD8⁺ T cells may play an important role in controlling the normal development of tolerance.