Serologic, cellular, and molecular evidence supports the concept of extreme complexity within the HLA-D region. To study the complexity and fine specificity of the HLA-D region at the level of T-cell recognition, a panel of T-cell clones was generated against alloantigens associated with HLA-DR1 through -DRw8. After initial screening of more than 800 clones, 89 representative lines were selected for extensive testing against 204 unrelated stimulator cells. Clone-by-clone correlation analyses were performed to test whether any clones recognized similar or identical epitopes. In addition, clonal reactivity patterns were correlated with known HLA specificities. Twelve clusters of clones were identified with similar reactivity patterns using clone-by-clone correlation analysis. Some groups were significantly correlated with specificities associated with various D-region haplotypes; others had no significant correlation with any defined D-region specificity. Five general types of clones obtained in our study can be categorized as follows: Those recognizing epitopes clearly demonstrating a primary association with the classically defined D-region molecules against which the clones were primed. Clones recognizing epitopes associated with one of the priming antigens and also with another unrelated D-region specificity. Clones detecting epitopes which showed significant correlation with D-region molecules totally different from those against which they were originally primed. Clones with limited reactivity in population studies and no correlation with defined D-region molecules. Clones recognizing class I-associated epitopes.