Cutaneous T-cell lymphomas (CTCL) are a heterogeneous group of lymphoproliferative disorders. We investigated the variable region (V beta) of the T-cell receptor (TCR) repertoire in CTCL and compared it to the V beta repertoire in normal and eczematous skin. We used a panel of 21 anti-V beta antibodies and investigated 84 biopsies of 71 CTCL patients (4 parapsoriasis en grandes plaques (PA), 1 lymphomatoid papulosis, 29 mycosis fungoides (MF), 13 Sezary syndrome (SS), 1 CD8+ CTCL, 11 pleomorphic CTCL (PLEO), 12 CTCL nor classified). Six biopsies of normal skin and 6 of eczematous skin lesions served as controls. We determined the frequency of the V beta in normal and inflamed skin and compared it to the percentage of the respective V beta in the malignant clone of the CTCL patients. The percentage of the V beta positive CD4+ cells in relation to the total number of T cells in normal skin and inflamed skin differed from the distribution of the V beta families in the peripheral blood mononuclear cells (PBMC). Out of 71 CTCL cases, the clone was identified in 23 (32%). We identified the following clones: 1 V beta 3.1 (16MF), 7 V beta 5.1 (1 CD8+ CTCL, 1 CTCL not classified, 1 MF, 1 PA, 3 SS), 1 V beta 6.7 (1 SS), 7 V beta 8.1/8.2 (2 CTCL not classified, 1 PLEO, 2 MF, 2 SS), 1 V beta 12.1 (1 PLEO), 3 V beta 17.1 (2 CTCL not classified, 1 MF), 2 V beta 22.1 (1 CTCL not classified, 1 MF), 1 TCR delta (SS). The frequency of the malignant clone V beta usage corresponded well to the repertoire of V beta in eczematous skin but not to the repertoire in PBMC. In 6 patients, the malignant clone was mainly localized in the epidermis. In 17 cases, the clone-specific cells were distributed in epidermis and dermis equally. A retrospective analysis showed that preferential epidermal homing of the clone was associated with a non-aggressive clinical course. The V beta usage of CTCL and eczema suggests a special cutaneous microenvironment which might be co-created by certain (bacterial?) superantigens. A preferential epidermal homing of the clone might have prognostic implications.