The knowledge of tumor-associated antigens is required for most types of immunotherapy and can substantially facilitate diagnosis. To identify potential tumor-associated genes expressed in cutaneous T-cell lymphoma (CTCL), we used three complementary strategies: antigens which elicit a humoral immune response in CTCL patients were detected by serological analysis of a recombinant cDNA expression library. cDNAs differentially expressed in CTCL but not peripheral blood monocytes were identified by comparative cDNA hybridization and suppression subtractive hybridization. We identified 43 genes selectively expressed by CTCL cells, that have not yet been described in the context of CTCL development, but most of which had been reported to be associated with cancer. Expression analysis by database mining and subsequently RT-PCR on selected clones confirmed their selective expression in CTCL tissues. Serological tests showed that 15 clones were recognized by sera of CTCL patients but not of healthy donors. Analysis of serological tests for 11 clones using serum antibody detection array (SADA) and 100 sera of controls and CTCL patients each revealed up to 5% reactive sera in the tumor group. The expression pattern of the detected clones and their immunogenicity demonstrates that they might be relevant for the understanding of CTCL and suggests particularly three clones, HD-CL-41 (DRAK2), HD-CL-49 (nudC) and HD-CL-12 (ZNF195) for further analysis with respect to their prognostic and therapeutic value for CTCL.