We studied HLA-DQB1 haplotypes in 103 unrelated multiple sclerosis (UMS) patients and in 26 related (RMS) patients from 12 families from Sardinia, Italy, where the disease was associated with the HLA-DR4 allele. Using polymerase chain reaction and allele-specific oligonucleotide probes, we found in UMS an increased frequency of the DQB1 *0201 (p = 0.010) and DQB1 *0302 (p = 0.025) alleles, whereas the DQB1 *0301 allele was significantly decreased (p = 0.027). In RMS, only the DQB1 *0302 allele was increased (p = 0.047), and no difference was found in the DQB1 *0301 allele. For DQB haplotypes, an increased frequency of DQB1 *0302/*0502 (p = 0.026) and a decreased frequency of DQB1 *0201/*0601 (p = 0.009) and DQB1 *0502/*0502 (p = 0.025) was found in UMS patients, whereas RMS patients showed an increased frequency of DQB1 *0301/*0302 (p = 0.005). Because DQB1 *0201 and *0302 alleles are increased in Caucasian MS patients, where the disease is related to HLA-DR2 and where a primary association with the HLA-DR2, DQB1 *0602 allele has been reported, we conclude that Caucasian and Sardinian populations share HLA-DQB1 *0201 and *0302 alleles in genetic susceptibility to MS.