The human HLA‐DQ8 (A1*0301/B1*0302) allelic product manifests a strong association with insulin‐dependent diabetes mellitus (IDDM). Previous biochemical studies of the major histocompatibility complex (MHC) class II I‐A^g7 protein of IDDM‐prone non‐obese diabetic mice produced controversial results. To better define the biochemical properties of IDDM‐associated MHC class II molecules, we analyzed DQ8 proteins, in comparison to other DQ allelic products, by partially denaturing sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS‐PAGE). We now report that DQ8 proteins have a normal peptide occupancy and lifespan in cells. Similar to I‐A^g7, DQ8 proteins formed only a minor fraction of SDS‐stable complexes with peptides. Although this phenotype was not unique to DQ8, some DQ allelic products such as IDDM‐protective DQ6 proteins were SDS resistant. The DQ9 allelic product, differing from DQ8 only at position (P) β57, was SDS stable, suggesting that non‐Asp residues at β57 might decrease the SDS stability of DQ proteins. We identified a single peptide which specifically induced an SDS‐stable conformation in DQ8 as well as in I‐A^g7 molecules. The residues at anchor P1 in this peptide were found to influence the SDS stability of both molecules. Together with our previous observation of similar binding motifs of I‐A^g7 and DQ8, these results demonstrate an overall biochemical similarity of mouse and human diabetes‐associated MHC class II molecules. This similarity might contribute to a common immunological mechanism of IDDM in both species.