Although the human leukocyte antigen DR2/DQw1 allele has been associated with multiple sclerosis, studies of DR2/DQw1 inheritance in multiple sclerosis multiplex families have yielded conflicting results. We examined this question in "high-incidence" families, defined as families with more than 50% of siblings affected. DR2/DQw1 allele frequencies were significantly increased, particularly in mothers and affected siblings (p < 0.0001). The transmission of DR2/DQw1 from both parents was more frequent in affected offspring (p = 0.005). While evidence for segregation of disease with a particular parental allele was lacking in most families, the frequency of haplotype sharing was higher in affected sib pairs (p < 0.01).