The HLA class II haplotype DR15,DQ6,Dw2 is associated with an increased risk for multiple sclerosis (MS). It has previously been shown that this haplotype extends to the HLA-DQA2 locus but not to the HLA-DP subregion. We report the distribution in 148 MS patients and 158 healthy controls of Taq I restriction fragments of the C4, cytochrome P-21 (CYP21), and HLA-B genes. Approximately 90% of the DR15,DQ6,Dw2 haplotypes extend to the C4/CYP21 loci and 50% to the HLA-B locus, indicated by a significant association of the haplotype with restriction fragments of these loci. However, there was no independent association in MS patients with these genes. This indicates that the susceptibility to MS is coded for by genes within or close to the HLA-DR-DQ subregion. Furthermore, the delineation of the DR15,DQ6,Dw2 haplotype is very similar in MS patients and control subjects. This observation supports the hypothesis that "normal" genes, common to all carriers of the DR15,DQ6,Dw2 haplotype, confer the increased genetic susceptibility to MS associated with this haplotype.