Omenn syndrome comprises a rare form of combined immunodeficiency with TH2-type features of eosinophilia and elevated IgE. Previous studies have led to reports of restricted heterogeneity in the T lymphocyte repertoire, and in vitro cloned T lymphocytes have been shown to produce IL-4 and IL-5. We hypothesized that (1) T cell receptor beta V(D)J DNA sequence analysis would confirm and further define the putative restricted heterogeneity, and (2) increased production of IL-4 and IL-5 should be found in nonstimulated T lymphocytes, if the molecular pathogenesis of Omenn syndrome is an uncontrolled TH2 state. We report the results of molecular analyses of T lymphocytes from an untreated 3-month-old patient. Oligoclonal T cell receptor beta variable gene usage was found. Sequence analysis revealed sets of identical V(D)J sequences, each in-frame, with apparently normal N-diversification and no obvious antigen combining site motif. From fresh, nonstimulated lymphocytes, proinflammatory TH1 cytokines could be detected, but TH2 cytokines could not, so that a simple TH1/TH2 paradigm cannot explain the eosinophilia and elevated IgE in Omenn syndrome. Our studies fully document for the first time at the molecular level that clonally expanded populations of T lymphocytes are present in Omenn syndrome.