BACKGROUND & AIMS: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is the best-characterized form of a rare entity called autoimmune enteropathy (AIE). IPEX syndrome is due to mutations in the FOXP3 gene, a transcription factor essential for the development and function of the natural regulatory CD25(+)CD4(+) T cells. We studied a female patient with a polyautoimmune AIE syndrome resembling a mild form of IPEX syndrome but associated with recurrent bacterial infections and mild hypogammaglobulinemia. We hypothesized that this syndrome combined a deficit of FOXP3(+) cells and other lymphocyte populations. METHODS: We analyzed the major lymphocyte subsets and the FOXP3(+) regulatory system in blood samples obtained during the 2-year period that followed the last autoimmune manifestation. RESULTS: The patient had severe naive T lymphopenia and a major deficit of FOXP3(+)CD4(+) T cells, both in circulation and in the highly inflamed intestinal mucosa, but mutations in the FOXP3 locus were excluded. The blood FOXP3(+) pool was devoid of CD25(high) cells, but the few regulatory CD25(+) cells were functional. Intrinsic defects in the expression of CD25, FOXP3, and interleukin 2 were excluded. Upon activation, a small subset of cells, presumably committed to regulatory function, sustained expression of CD25 and FOXP3. CONCLUSIONS: Peripheral T lymphopenia of both naive and natural regulatory T cells might be the consequence of defective thymic production or the short life span of exported T cells. This case sheds new light in the etiology of autoimmune manifestations in T-cell immunodeficiencies and in the heterogeneity of AIE.