Human narcolepsy-cataplexy, a sleep disorder associated with a centrally mediated hypocretin (orexin) deficiency, is tightly associated with HLA-DQB10602. Few studies have investigated the influence that additional HLA class II alleles have on susceptibility to this disease. In this work, 1,087 control subjects and 420 narcoleptic subjects with cataplexy, from three ethnic groups, were HLA typed, and the effects of HLA-DRB1, -DQA1, and -DQB1 were analyzed. As reported elsewhere, almost all narcoleptic subjects were positive for both HLA-DQA10102 and -DQB10602. A strong predisposing effect was observed in DQB10602 homozygotes, across all ethnic groups. Relative risks for narcolepsy were next calculated for heterozygous DQB10602/other HLA class II allelic combinations. Nine HLA class II alleles carried in trans with DQB10602 were found to influence disease predisposition. Significantly higher relative risks were observed for heterozygote combinations including DQB10301, DQA106, DRB104, DRB108, DRB111, and DRB112. Three alleles—DQB10601, DQB10501, and DQA101 (non-DQA10102)—were found to be protective. The genetic contribution of HLA-DQ to narcolepsy susceptibility was also estimated by use of gamma statistics. Results indicate that complex HLA-DR and -DQ interactions contribute to the genetic predisposition to human narcolepsy but that additional susceptibility loci are also most likely involved. Together with the recent hypocretin discoveries, these findings are consistent with an immunologically mediated destruction of hypocretin-containing cells in human narcolepsy-cataplexy.