HLA-DS molecules, the human homologs of murine I-A molecules, were analyzed and compared to DR molecules by two-dimensional gel analysis. These analyses allowed us to define six forms of DS molecules, suggesting that DS molecules were as polymorphic as DR molecules. The supertypic specificities, MT1 and MB3 were localized to DS molecules, whereas MT3 appeared to represent a crossreactive determinant present on products of two different loci encoding Ia-like molecules in man, a DS4 molecule and a DR7-like molecule. These studies also revealed that MT1 molecules isolated from DR1 and DR2 cell lines were different, as were MB3 molecules isolated from DR4 and DR5 cell lines. Extensive crossreactions between DR and DS molecules were observed by using several monoclonal antibodies. This sharing of epitopes between products of different loci for human Ia molecules has important functional implications.