Histologic, histochemical, and histoenzymatic investigations of nine cases of Omenn's disease showed generalized lymphoid depletion, including B cells and all T-cell subpopulations; an apparent proliferation of alpha-naphthyl acetate esterase-, acid phosphatase-, OKM1-positive macrophages and T6 interdigitating cells; a thymic hypoplasia with arrest of hassallian epithelial maturation; starlike fibrinous deposits in the bone marrow; and extensive cutaneous lesions characterized by hyperkeratosis, apoptotic cell death associated with the intraepidermal presence of T4+ and T8+ cells, localized necrosis of the basement membrane, expression of Ia antigens by malpighian cells, and progressive loss of the T6+ Langerhans' cells. These lesions, mainly the skin and bone marrow changes, are reminiscent of those observed in acute graft versus host reaction. Although a blood chimerism has never been demonstrated, these pathologic observations support the hypothesis of graft versus host disease in a primary cellular immunodeficiency and the persistence of the proliferating maternal cells in the peripheral target organs.