HLA-DR allele subtypes in multiple sclerosis (MS) individuals in Spain were determined by restriction fragment length polymorphism (RFLP) analysis. The well-established association of DRw15, DQw6, Dw2 alleles and MS susceptibility was confirmed. The strength of its association, however, was relatively weak in our MS population and no involvement with any other DR allele was observed. DQw6 increase correlated with the elevation of the involved DR2 subtype. The hypothesis that MS-associated susceptibility genes may be more closely associated with the DQ than the DR region was not supported by our findings which, on the other hand, could be in concordance with the concept that multiple genes contribute to MS susceptibility.