The association with HLA-DRB1 alleles was tested in 609 Continental Italian MS patients and 836 controls. The phenotype frequency of DRB1*15 in the patients was significantly higher (0.316 vs. 0.112; p(c)<10(-6); Odds Ratio (OR)=3.64) with no dose effect. DRB1*10 was also significantly increased (OR=2.19; p(c)=0.047) and DRB1*07 decreased (OR=0.60; p(c)=1.3 x 10(-3)) independently of DR15 and of each other. We did not detect an influence of the DR phenotype on disease course, age at onset/diagnosis, gender or familiarity. No association with Class I was detected in a random subset of patients and controls. A comparison of the HLA association data in Northern and Southern European populations shows a parallel between disease prevalence and DR15 frequency.