Cutaneous T-cell lymphoma (CTCL) encompasses leukemic variants (L-CTCL) such as Sézary syndrome (SS) and primarily cutaneous variants such as mycosis fungoides (MF). To clarify the relationship between these clinically disparate presentations, we studied the phenotype of T cells from L-CTCL and MF. Clonal malignant T cells from the blood of L-CTCL patients universally coexpressed the lymph node homing molecules CCR7 and L-selectin as well as the differentiation marker CD27, a phenotype consistent with central memory T cells. CCR4 was also universally expressed at high levels, and there was variable expression of other skin addressins (CCR6, CCR10, and CLA). In contrast, T cells isolated from MF skin lesions lacked CCR7/L-selectin and CD27 but strongly expressed CCR4 and CLA, a phenotype suggestive of skin resident effector memory T cells. Our results suggest that SS is a malignancy of central memory T cells and MF is a malignancy of skin resident effector memory T cells.