The HLA-DR2/Dw2 haplotype is associated with multiple sclerosis (MS) in the North American Caucasian population. HLA-DRB, -DQA, and -DQB N-terminal domain sequences derived from amplified cDNA in a series of North American Caucasian MS patients were examined to determine if unique or rare class II alleles could be found. In addition, class II allelic sequences were analyzed from clinically discordant, HLA-genoidentical siblings from a multiplex MS family. All alleles observed, whether from HLA-DR2/Dw2 positive or negative individuals, were identical to those most commonly expressed in the general population. These data demonstrate that, if HLA class II truly confers susceptibility to MS, commonly expressed alleles are involved.