An unusual form of severe combined immunodeficiency in children from two different families was associated with absence of CD8+ T lymphocytes and normal numbers of CD4+ T lymphocytes that did not respond to stimulation by non-specific mitogens, specific antibodies against T cell receptor or specific antigens. The defect in the CD4+ cells was bypassed by activating agents which are independent of the T cell receptor. The combination of an activation defect and selective depletion of CD8+ T lymphocytes suggests that the defective pathway is important in the differentiation of immature thymocytes as well as the proliferation of mature lymphocytes.