Narcolepsy, a sleep disorder characterized by excessive daytime sleepiness, cataplexy and rapid eye movement sleep abnormalities, is tightly associated with human leukocyte antigen HLA-DQB1*06:02. DQB1*06:02 is common in the general population (10-30%); therefore, additional genetic factors are needed for the development of narcolepsy. In the present study, HLA-DQB1 in 664 Japanese narcoleptic subjects and 3131 Japanese control subjects was examined to determine whether HLA-DQB1 alleles located in trans of DQB1*06:02 are associated with narcolepsy. The strongest association was with DQB1* 06:01(P = 1.4 x 10(-10), odds ratio, OR = 0.39), as reported in previous studies. Additional predisposing effects of DQB1*03:02 were also found (P = 2.5 x 10(-9), OR = 1.97). A comparison between DQB1* 06:02 heterozygous cases and controls revealed dominant protective effects of DQB1* 06:01 and DQB1*05:01. In addition, a single-nucleotide polymorphism-based conditional analysis controlling for the effect of HLA-DQB1 was performed to determine whether there were other independent HLA associations outside of HLA-DQB1. This analysis revealed associations at HLA-DPB1 in the HLA class ll region (rs3117242, P = 4.1 x 10(-5), OR = 2.45; DPB1*05:01, P = 8.1 x 10(-3), OR = 1.39). These results indicate that complex HLA class ll associations contribute to the genetic predisposition to narcolepsy.