ONE mechanism ensuring self tolerance of T cells is the clonal deletion of thymocytes bearing αβ T-cell receptors^1–4. The stage of thymocyte development at which the interaction with antigen-presenting cells (APCs) leads to deletion, however, has not been determined directly. Indirect evidence suggests that intrathymic APCs induce deletion of CD4⁺8⁺ thymocytes^3–6 (which die by apoptosis⁷) but deletion at less⁸ and more mature⁹ developmental stages has also been implied. It is also not clear if clonal elimination of thymocytes can be triggered by peripheral antigens carried on extrathymic APCs migrating through the thymus¹⁰. Here we show antigen-specific induction of apoptosis in CD4⁺8⁺ thymocytes cultured in suspension, by thymic as well as splenic APCs. Thus the recognition of antigen by CD4⁺8⁺ thymocytes may lead to deletion, suggesting that this is the central mechanism of tolerance induction, which is not limited by the antigen-presenting ability of the thymic stroma.