Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system unsurpassed for variability in disease outcome. A cohort of sporadic MS cases ( n = 163), taken from opposite extremes of the distribution of long-term outcome, was used to determine the role of the HLA-DRB1 locus on MS disease severity. Genotyping sets of benign and malignant MS patients showed that HLA-DRB1 * 01 was significantly underrepresented in malignant compared with benign cases. This allele appears to attenuate the progressive disability that characterizes MS in the long term. The observation was doubly replicated in ( i ) Sardinian benign and malignant patients and ( ii ) a cohort of affected sibling pairs discordant for HLA-DRB1 * 01 . Among the latter, mean disability progression indices were significantly lower in those carrying the HLA-DRB1 * 01 allele compared with their disease-concordant siblings who did not. The findings were additionally supported by similar transmission distortion of HLA-DRB1 * 04 subtypes closely related to HLA-DRB1 * 01. The protective effect of HLA-DRB1 * 01 in sibling pairs may result from a specific epistatic interaction with the susceptibility allele HLA-DRB1 * 1501 . A high-density (>700) SNP examination of the MHC region in the benign and malignant patients could not identify variants differing significantly between the two groups, suggesting that HLA-DRB1 may itself be the disease-modifying locus. We conclude that HLA-DRB1 * 01 , previously implicated in disease resistance, acts as an independent modifier of disease progression. These results closely link susceptibility to long-term outcome in MS, suggesting that shared quantitative MHC-based mechanisms are common to both, emphasizing the central role of this region in pathogenesis.