Acute Disseminated Encephalomyelitis (ADEM) is an acute, multifocal, monophasic, inflammatory demyelinating disease of the central nervous system that affects predominantly children. Aim of the study was to evaluate the distribution of Human Leukocyte Antigen (HLA) class II haplotype in adult ADEM patients, in order to better characterize this rare clinical entity. Six patients (3 males and 3 females; median age 50 years) with ADEM were retrospectively studied in our Neurology Unit; 29 healthy subjects (8 males and 21 females, mean age 43.4±14.3) were the control group. All the study subjects were molecularly typed for HLA class II haplotype. The frequencies of HLA-DRB1*16 (17% vs 3% in control group; Py=0.02) and HLA-DQB1*05 (42% against 24% in the control group; Py=0.010), as well as the association HLA-DRB1*16/HLA-DQB1*05 were significantly increased in ADEM population compared to the control group. The frequencies of allelic association between 13-04 (P < 0.01) and homozygosis 14 (P < 0.05) alleles at HLA-DRB1* locus and 05-02 (P < 0.05) alleles at HLA-DQB* locus also were increased in ADEM patients. Our preliminary data provide further evidence that the HLA-DR/DQ haplotypes may be involved in susceptibility to immunomediate demyelinating diseases of central nervous system in the Caucasian population.