BACKGROUND: Kleine-Levin syndrome (KLS) is a rare disorder of unknown etiology. Pathophysiologic hypotheses include a hypothalamic dysfunction and abnormalities in the central serotonin and dopamine metabolism. Several clinical symptoms also suggest an underlying autoimmune process. OBJECTIVE: To systematically investigate patients with KLS with reference to the available hypotheses. METHODS: The authors collected clinical, polysomnographic, CSF, CT, and MRI records and analyzed gene polymorphisms of HLA-DQB1, tryptophan hydroxylase (TpH), and catechol-O-methyltransferase (COMT) in 30 unrelated patients with KLS and their families. The genotype data were contrasted with data from a normal control population. RESULTS: Only human leukocyte antigen (HLA)-DQB1*0201 allele frequency was significantly increased in patients with KLS. Three patients with KLS but none of the control subjects were DQB1*0201 homozygous. Two affected subjects from the same family were DQB1*0201 homozygous. In 17 DQB1*0201 heterozygous parents, 11 (64.7%) had transmitted this allele, suggesting a preferential transmission. CONCLUSION: These findings, together with the young age at onset, the recurrence of symptoms, and the frequent infectious precipitating factors, suggest an autoimmune etiology for Kleine-Levin syndrome.