We have previously shown that autologous T cells recognize leukaemic cells from patients with chronic lymphocytic leukaemia (B‐CLL) in an MHC class I‐ and/or II‐restricted manner. A candidate recognition structure might be the tumour cell‐derived Ig VH complementarity‐determining region (CDR)3. Three patients with B‐CLL were analysed for the presence of autologous T cells recognizing the tumour‐specific VH‐CDR3 region. The VH region was shown to be mutated in all three patients. In two patients, a VH‐CDR3‐specific T‐cell response was detected by proliferation assay, as well as by γ‐interferon (IFN) production. The responses could be inhibited by monoclonal antibodies against MHC class II, but not MHC class I. In the third patient, a VH‐CDR3 proliferative response was detected, which could be inhibited by an anti‐MHC class I monoclonal antibody, but not by anti‐MHC class II antibodies. No γ‐IFN response could be detected in this patient. In no patient was an interleukin (IL)‐4 response noted. Thus, in patients with B‐CLL, naturally occurring T cells recognizing the tumour‐unique VH‐CDR3 region are present.