Cutaneous T-cell lymphomas (CTCL) are mainly comprised of two variants: mycosis fungoides (MF) with CD4 þ tumor cells confined to the skin and the leukemic Sé zary syndrome with tumor cell spread to the blood. In this study, we investigated cutaneous expression of the regulatory T-cell (T reg ) marker FOXP3 in 30 CTCL patients. Immunohistochemical analysis revealed significantly lower numbers of CD4 þ FOXP3 þ cells within the dermal lymphomononuclear infiltrate of Sé zary patients (16% FOXP3 þ cells of CD4 þ cells) in contrast to MF (43% FOXP3 þ cells (Po0.05)) and rare types of CTCL (45% FOXP3 þ cells). Furthermore, CD4 þ FOXP3 þ T cells were also markedly reduced in the CD4 þ population within the peripheral blood of Sé zary patients compared to controls as determined by fluorescence-activated cell sorter, quantitative PCR and functional analyses. The data support the conclusion that the neoplastic cells in CTCL do not express the T reg marker FOXP3. Our data also identify Sé zary syndrome as, to our knowledge, the first reported neoplastic disease with a clear reduction in T reg numbers within the CD4 þ population. This lack of T reg might account for the more aggressive nature of Sé zary syndrome compared with other CTCL.