We describe two sets of epitopes present in HLA-DP molecules; they were identified with alloantibodies from clinical serum samples. Specificity was determined using fluorescent beads coated with single antigens and detected in a Luminex platform. Of the patients with anti-HLA class II antibodies, 18% had anti-DP antibodies; among these, 24 of 32 patients (75%) had antibodies against the dimorphic epitope sets described here. Residues 56-A and 56-E divide DPB1 alleles into two mutually exclusive and collectively exhaustive groups. These groups have distinctive dimorphic epitopes that are detected by antibodies. Epitope P-001, identified by 2 sera, is defined by residue 56-A of the DPB subunit. Epitope P-002, identified by 9 sera, is defined by residue 56-E. Interlocus DRB1/DPB1 reactivity is associated with P-002, which is found in DRB1-DR11 alleles. Residues at DPB1 85-87-EAV define the P-003 epitope, whereas P-004 is defined by 85-87-GPM. This dimorphism also divides DPB1 alleles into two mutually exclusive and collectively exhaustive groups. In this study, 12 patient sera identified DP-003, and 1 identified DP-004. Two dimorphic systems account largely for the serologic features of the DP molecules, and these specificities were found in most clinical samples with anti-DP activity.