Omenn's syndrome (OS) is a severe immunodeficiency, characterized by clinical and laboratory features reminiscent of a T helper type‐2 (Th2) response. CD30, a member of the tumor necrosis factor receptor superfamily, has been found to be preferentially expressed by human T cell clones exhibiting a Th2‐like profile and function. We investigated whether there are derangement in CD30 expression in tissues, and/or abnormalities in soluble CD30 (sCD30) levels in the serum, or both, of three children with OS and one child with maternal engraftment and Omenn's‐like syndrome (OLS). Large proportions of tissue‐infiltrating T lymphocytes from all four patients expressed CD30, whereas in control tissues, including peripheral blood, CD30⁺ T lymphocytes were extremely few or absent. In addition, levels of sCD30 were abnormally increased in all patients' sera. T cell clones were generated from sorted CD30⁺ and CD30⁻ peripheral blood T cells of the patient with OLS who showed unusually high numbers of circulating CD30⁺ T lymphocytes. Most CD4⁺ T cell clones derived from CD30⁺ cells showed a Th2‐like cytokine profile, whereas the majority of clones generated from CD30⁻ T cells were Th1. These findings support the hypothesis that Th2 cells are involved in the pathogenesis of OS. Moreover, they provide evidence that detection of CD30⁺ T cells in tissues, increased levels of sCD30 in biological fluids, or both, reflect the presence of immune responses characterized by prevalent activation of T cells producing Th2 cytokines.