The clonal CD3(-)CD4(+) T-cell population characterizing lymphocytic variant hypereosinophilic syndrome (L-HES) persists for years, with a subgroup of patients ultimately progressing to T lymphoma. The molecular changes associated with the premalignant clone and the emergence of malignant subclones are unknown, precluding the development of targeted therapy for this HES variant. In this study, we used whole genome arrays to examine gene expression in the CD3(-)CD4(+) T cells and found that 850 genes were differentially regulated during chronic disease compared with CD3(+)CD4(+) T cells from healthy donors. Changes in the expression of 349 genes were altered in association with the clinical progression from chronic L-HES to T lymphoma in 1 patient, with 87 of 349 genes representing further changes in genes whose expression was altered in all chronic disease patients (87 of 850). Array analysis after CD2/CD28-mediated activation revealed that the major gene expression changes observed in the CD3(-)CD4(+) T cells do not reflect activation induced alterations but rather pathways involved in T-cell homeostasis, including transforming growth factor-beta signaling, apoptosis, and T-cell maturation, signaling, and migration. Examination of microRNA expression in the CD3(-)CD4(+) T cells from patients with chronic disease identified 23 microRNAs that changed significantly, among which miR-125a further decreased in association with one patient's evolution to T lymphoma.