To analyze DR2 haplotypes as recognized by alloreactive T cells, lymphocytes from a DR7; DQw2 homozygous donor were cocultured with irradiated lymphocytes that were DRw15, DR7; DQw6, DQw2 heterozygous. In this report, we focus on two HLA-DQ-specific T-cell clones obtained from this priming. These two clones (c3518 and c3523) responded to the positive control (original stimulator) and five of 66 panel donors. Three of these donors typed DRw15, DR7; DQw6, DQw2, as did the positive control. One stimulatory donor typed DRw15, DR7; DQw6, DQw9 and one stimulatory donor typed DRw14, DR7; DQw5, DQw2. Oligonucleotide typing revealed that recognition by the clones depended on the simultaneous presence of the DQB1*0602 gene on one haplotype and DRB1*0701 or DQA*0201 on the other. The hypothesis that c3518 and c3523 recognize an HLA class II product that results from the combination of two different HLA haplotypes was further confirmed in family studies. In three families, it was shown that the DRw15, DR7; DQw6, (DQw2 or DQw9)-positive individuals were recognized, whereas the cells carrying either DRw15; DQw6, DR7; DQw2, or DR7; DQw9 were nonstimulatory. Our results can be explained in two ways: (a) the T cells recognize a class II dimer that results from trans-complementation of DQA1*0101 and DQB1*0602, and (2) the T cells recognize a DR7-derived peptide that is presented by DQw6.