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HLA-DQ class II molecules are complex heterodimers in which polymorphic alpha- and beta-polypeptides form noncovalent associations leading to cell surface expression. Using gene transfer with retroviral vectors, we demonstrate that surface expression of heterodimers among various DQ alpha and -beta polypeptides is not universal. Two types of allele-specific constraints were found: DQ beta chains that are associated with the DQw1 specificities do not form stable cell surface heterodimers with DQ alpha chains encoded on haplotypes that are associated with DQw2, DQw3, or DQw4. Similarly, surface expression of heterodimers composed of DQw2- or DQw3-associated DQ beta chains and DQw1 DQ alpha chains were not detected. The formation of mixed isotype heterodimers also showed allelic preference: DR alpha/DQw1 beta dimers were detected on the cell surface, but DR alpha/DQw3 beta dimers were not. Failure to express class II heterodimers on the cell surface was apparently due to either inefficient assembly of the alpha- and beta-chains or retention of the mismatched dimers in an intracellular compartment. DQ beta cDNA encoding DQw1- and DQw3-associated beta-polypeptides were modified to create chimeric expression vectors in which portions of the DQ beta polypeptides were exchanged between different alleles. The resulting chimeric DQ beta polypeptides were tested for their ability to form stable heterodimers with different DQ alpha polypeptides. A cluster of polymorphic amino acid residues encoded by the 3' end of the DQB1 second exon, corresponding to residues 60 to 91 in the DQ beta polypeptide, were found to be critical determinants constraining stable cell surface heterodimer formation among preferential alpha- and beta-combinations.