Several studies have shown familial incidence of narcolepsy and idiopathic central nervous system (CNS) hypersomnia. HLA antigen studies performed in mongoloid and caucasoid narcoleptic patients on the A, B, and C loci have yielded conflicting results. The aim of this study is to document a possible association between the HLA system, including the DR locus and excessive daytime somnolence. Thirty-one narcoleptic patients and 10 idiopathic hypersomniac patients were selected and typed for 54 HLA antigens. A family with narcoleptic members in 3 generations was also studied. HLA-DR2 was found in 100% of narcoleptic patients. The frequency of HLA-A3 and B7, which are in linkage disequilibrium with DR2 was also increased in this group. Idiopathic hypersomniac patients showed an increase of HLA-Cw2, DR5, and B27, three antigens known to be in linkage disequilibrium. In the family study, narcoleptic patients were also HLA-DR2; moreover, 3 subjects, one of whom was narcoleptic, were HLA-DR2 as a result of recombination (i.e., genetic crossing-over). These results locate the hypothetic gene associated with narcolepsy more precisely, and indicate that narcolepsy and idiopathic CNS hypersomnolence are two different entities.