BACKGROUND Family and population studies have shown the existence of genetic susceptibility to have multiple sclerosis (MS). The genes of the HLA system have been the only genetic markers for this tendency to have been confirmed in multiple studies in different countries. A relation has also been found between certain HLA genes and the clinical course or paraclinical parameters of MS. METHODS In this article we first analyze the structure, function, typing and association of illnesses with the HLA system and their relation with MS. Subsequently we review the articles published or reported on the HLA-MS association in the Spanish population. CONCLUSIONS MS is generally associated with the DR15/DQ6 haplotype (subtypes of DR2/DQ1) in the Spanish population. There may be minor ethnic differences in some regions which explain other associations found. Although the Spanish studies on the association of HLA with clinical and paraclinical factors of MS require confirmation in samples with larger number of patients, the primarily progressive forms and those with a worse prognosis tend to be associated with DR4 and the benign forms with DR2. The DRw 13 (DR6) seems to be a protective allele. The presence of DR2 may be a marker for the development of MS after an optic neuritis.