A 5-year follow-up study was performed on 70 Caucasian patients presenting with isolated neurological syndromes of the optic nerve, brain stem, or spinal cord to assess the risk of progression to MS. The influence on patient prognosis of HLA-DR and -DQ alleles and presentation with disseminated brain lesions, demonstrated by MRI scanning, was determined. Clinical progression to MS was observed in 61% of optic neuritis patients, 50% of patients with a brain-stem syndrome, and 35% of patients with a spinal cord disturbance. MS and the isolated clinical syndromes were positively associated with DRB1*1501, DQA1*0102, and DQB1*0602; the frequency of these alleles in the latter group was intermediate between that seen in MS patients and healthy controls. Conversion to MS was positively associated with the DRB1*1501.DQA1*0102.DQB1*0602 haplotype, but the influence of HLA was only significant in patients with disseminated brain lesions at presentation (MRI positive); MS developed in 86% of MRI-positive, DRB1*1501-positive patients compared with 55% of MRI-positive, DRB1*1501-negative patients (p < 0.025). The data suggest that these HLA alleles are involved in susceptibility to initial demyelinating lesion formation and are important in the subsequent development of MS in MRI-positive patients.