An autoimmune background is thought to characterize the families of multiple sclerosis (MS) patients, but disease patterns and HLA–DR association seem to vary considerably among different ethnic groups. We investigated the prevalence of autoimmune diseases in 245 MS patients and 245 age– and sex–matched normal controls (NC), originating from and living in North–east Italy, and their first degree relatives, using a case–control method. Further, HLA–DRB1 expression was analysed in MS and NC. The following significant findings were observed: 1) a significant excess of autoimmunity in firstdegree relatives of MS patients (p = 0.000), 2) an association of MS with Type 1 diabetes mellitus (T1DM) (p = 0.02), 3) an increase in DR4 expression (namely DRB1*0401) in MS patients from families with multiple autoimmune pathology compared with reference MS patients (p=0.02) and NC (p=0.01).We conclude that the risk of autoimmune disease is higher in first–degree relatives of MS patients and that disease association and HLA–DR expression in North–east Italy differs from other geographic regions of Europe.