Sézary syndrome (SS) is an aggressive cutaneous T cell lymphoma with pruritic skin inflammation and immune dysfunction, driven by neoplastic, clonal memory T cells in both peripheral blood and skin. To gain insight into abnormal gene expression promoting T cell dysfunction, lymphoproliferation and transformation in SS, we first compared functional transcriptomic profiles of both resting and activated CD4CD45RO T cells from SS patients and normal donors to identified differential expressed genes. Next, a meta-analysis was performed to compare our SS data to public microarray data from a novel benign disease control, lymphocytic-variant hypereosinophilic syndrome (L-HES). L-HES is a rare, clonal lymphoproliferation of abnormal memory T cells that produces similar clinical symptoms as SS, including severe pruritus and eosinophilia. Comparison revealed gene sets specific for either SS (370 genes) or L-HES (519 genes), and a subset of 163 genes that were dysregulated in both SS and L-HES T cells compared to normal donor T cells. Genes confirmed by RT-qPCR included elevated expression of PLS3, and only in SS, while mRNA was increased only in L-HES. was increased in both diseases. In an L-HES patient who progressed to peripheral T cell lymphoma, the malignant transformation identified increases in the expression of , , and , which are highly expressed in SS, suggesting that these genes contribute to neoplastic transformation. In summary, we have identified gene expression biomarkers that implicate a common transformative mechanism and others that are unique to differentiate SS from L-HES.