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 first-degree 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.