The X-ray crystal structure of a complex between the human class II major histocompatibility complex (MHC) protein HLA-DRL and a bispyrrolinone-peptide hybrid ligand has been determined to 2.7 Angstrom resolution The bispyrrolinone segment of the ligand closely mimics the polyproline type II conformation of peptide ligands bound to class LI MHC molecules, emphasizing the considerable versatility of this peptidomimetic scaffold. Most hydrogen bonds conserved in all peptide/class II complexes are formed, and the side chains of the bispyrrolinone segment project into the same spaces as those occupied by side chains of bound peptides. Molecular modeling used in the design of the hybrid ligand was remarkably accurate in predicting the observed molecular interactions.