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In order to deduce the predominant haplotypes in Japanese narcoleptics, we have studied a total of 111 Japanese patients with narcolepsy and six multiple-case families for HLA class I and class II antigens, and for class III HLA-linked complement markers. In Japanese narcoleptics, the most frequent haplotypes were B35-DR2, B15-DR2, and B51-DR2. These haplotypes were rare in normal Japanese population. In contrast, the most frequent haplotype of HLA-DR2 in normal Japanese, A24-C blank-Bw52-C4A*2 B*Q0-BF *S-C2*C-DR2-DQw1, had a decreased frequency to one-third of the normal controls. Haplotypes B35-DR2, B15-DR2, and B51-DR2, which were more frequent among Japanese narcoleptics, were different from the haplotype found more frequently among Caucasoid narcoleptics, A3-Cw7-B7-DR2-DQw1. Haplotype analysis on six families showed that B35-DR2 and other rare haplotypes in normal Japanese were associated with narcolepsy. There were four cases without any signs of narcolepsy among 19 subjects with the disease susceptibility haplotypes. This finding suggests an incomplete penetrance of hypersomnia. Haplotype analysis of family members was also useful for the early detection of the high risk children to narcolepsy.