Narcolepsy is the disease disclosing the strongest association with the HLA system. Almost 100% of cases are associated with HLA-DR2 antigen. Moreover, narcolepsy is often characterized by the occurrence of sleep-onset REM (SOREM) periods. SOREM has also been demonstrated in major depression. To further investigate the relationship between SOREM and HLA-DR2, HLA-DR and HLA-DQ antigens were assessed in 50 research diagnostic criteria (RDC) major depressed patients. Depressed patients were elected for HLA typing on the basis of the presence of at least one SOREM period (n = 29) or three REM latencies above 50 min (n = 21) during three consecutives EEG nights recording. No significant differences were observed in the frequency of HLA-DR or HLA-DQ antigens between patients and controls. These results demonstrate a lack of association between SOREM and HLA-DR2 in major depression, and also do not confirm the presence of an association between antigens encoded by the HLA region of the chromosome 6 and major depressive illness.