We have previously experimentally analyzed the structural requirements for interaction between peptide antigens and mouse major histocompatibility complex (MHC) molecules of the d haplotype. We describe here two procedures devised to predict specifically the capacity of peptide molecules to interact with these MHC class II molecules (IA(d) and IE(d)). The accuracy of these procedures has been tested on a large panel of synthetic peptides of eukaryotic, prokaryotic, and viral origin, and also on a set of overlapping peptides encompassing the entire staphylococcal nuclease molecule. For both sets of peptides, IA(d) and IE(d) binding was successfully predicted in ~ 75% of the cases. This suggests that definition of such sequence 'motifs' could be of general use in predicting potentially immunogenic peptide regions within proteins.