We investigated the mechanism by which α/β T cells expand upon transfer to T cell–deficient host mice by injecting carboxyfluorescein diacetate succinimidyl ester–labeled T cells into mice depleted of T cells by sublethal irradiation. We found that CD4⁺ T cells divided when transferred to irradiated hosts and that the division of more than half of these cells required class II expression. However, division of transferred CD4⁺ T cells did not occur in irradiated hosts that expressed class II molecules occupied solely by the peptide responsible for thymic selection, indicating that peptides distinct from those involved in thymic selection cause the division of CD4⁺ T cells in irradiated mice. These data establish that class II–bound peptides control the expansion of CD4⁺ T cells transferred to T cell–deficient hosts and suggest that the same peptides contribute to the maintenance of T cell numbers in normal mice.