We analyzed HLA-A, -C, -B, -DR and -DQ specificities in 104 Italian multiple sclerosis patients and in 905 healthy controls. The frequencies of HLA-A23, A26, Cw4, DR3 and, especially DR5 antigens were significantly higher in multiple sclerosis patients than in controls. Patients with progressive course were characterized by high frequencies of B7, B8 and DR3 antigens: Cw1 and DRw11 shows a negative correlation with the extent of intrathecal IgG production. These data confirm that the HLA system may influence the clinical expression and the immune responses to the disease.