We wished to identify and characterize tumor-associated class I peptides which could potentially serve as immunogens for an immunoprotective CD8 response in cutaneous T-cell lymphoma (CTCL). Candidate idiotypic peptides were identified from the third complementarity determining region (CDR3) of the clonotypic T-cell receptor (TCR) expressed on malignant T cells and native class I peptides were identified from CTCL cells. Idiotypic peptides were designed by sequencing of patients' CDR3 and identifying 9 amino acid peptides that could be accommodated in the peptide-binding motif of the class I alleles. Three candidate idiotypic peptides were synthesized and tested by measuring release of tumor necrosis factor-alpha (TNF-alpha) from autologous CD8 cells. Native peptides were acid-eluted from class I molecules on CTCL lymphocytes, fractionated, tested in the TNF-alpha assay and sequenced. Two unique idiotypic peptides were specifically recognized by autologous CD8 cells from CTCL patients. In addition, a native peptide eluted from class I molecules of CTCL tumor cells was identified, in the protein data base, as a novel molecule with partial sequence homology to the conserved portion of the patient's TCR. This homology was used to construct an extended native peptide sequence that was immunogenic for CD8 cells from both CTCL patients. Our results demonstrate that peptides derived from the TCR can be used as tumor-specific immunogens that are recognized by CD8 cells. Moreover, novel class I peptides isolated from the tumor cell also serve as immunogens. These peptides might form the basis of an anti-tumor vaccine for immunotherapy of CTCL.