Cutaneous T cell lymphomas are considered to represent a clonal malignancy of mature T lymphocytes of the T helper memory subtype. A method enabling the direct identification of clonal malignant cells in tissue and, at the same time, identification of the surface molecules they express has not been available, however. We have developed an application of the FICTION technique (simultaneous fluorescence immunophenotyping and interphase cytogenetics) to be used on fresh blood, skin, and lymph node samples. A prerequisite for this method is the characterization of a moleculocytogenetic clone in order to select the proper probes. With this method, we demonstrate that the true malignant cells express CD3, CD4, and CD45RO in the blood, skin, and lymph nodes of two Sezary syndrome patients. The majority of these cells express also CD45RA (albeit of varying intensity) and CDw150. The cytokine expression pattern of the clonal cells in skin and lymph nodes was interleukin-2 and interferon-gamma negative and interleukin-4 positive. Interleukin-10 expression varied. The malignant cells did not express granzyme B, thus indicating that they do not have cytotoxic properties. Clonal cells with the same constant phenotype could be found even in lymph nodes with not yet morphologically identifiable malignant cells. This is the first report of the FICTION method applied directly on skin tissue. With this method we demonstrated that the chromosomally clonal cells in these two cases of Sezary syndrome could be intermediate forms between naïve CD45RA+ and CD45RO+ Th2 cells.