An association between multiple sclerosis (MS) and the human leukocyte antigen (HLA) complex, a dense cluster of genes on the short arm of chromosome 6, was first noted over 30 years ago. In Caucasian populations of Northern European descent, the DR15 haplotype (DRB1*1501-DQA1*0102-DQB1*0602) has been hypothesized to be the primary HLA genetic susceptibility factor for MS. However, studies of other populations have produced varying results. Thus, the authors reviewed the literature for articles on the association between the DR15 haplotype and MS. They identified 72 papers meeting the inclusion criteria: human genetic studies written in English that were published between 1993 and 2004 and that reported allele frequencies for HLA-DRB1*1501, HLA-DQA1*0102, or HLA-DQB1*0602 or the frequency of the DRB1*1501-DQA1*0102-DQB1*0602 haplotype. Most of the studies identified used a case-control design (n = 60), while the remainder used a family-based design (n = 22). In most of these papers, investigators reported a higher frequency of the DR15 haplotype and/or its component alleles among MS cases than among controls. However, the authors' confidence in these results is tempered by factors related to study design that may have biased the outcomes.