One-hundred and forty-six patients who had presented with optic neuritis but without evidence of demyelination elsewhere in the nervous system, and in whom no specific cause could be identified, were reassessed clinically between one month and twenty-three years after the onset. Fifty-eight patients (40 per cent) had developed MS. All 146 patients were HLA-typed. Three factors were identified which were significantly associated with the development of MS: positive typing for the HLA antigen BT 101, winter onset of the initial attack of optic neuritis in BT 101-positive patients only, and recurrent attacks of optic neuritis. The application of these results to the individual patient is of limited use. However, recurrent attacks of optic neuritis should be given the same significance in the clinical classification of MS as episodes of demyelination occurring elsewhere in the central nervous system in a patient with a previous attack of optic neuritis. The results suggest that optic neuritis is caused by two different environmental agents or groups of agents and that the agent which is most common in the winter leads to the development of MS in the genetically susceptible individual. The agent more common in the summer is much less likely to cause MS in either suscetible or non-susceptible individuals. The biological role of the HLA system in the handling of foreign antigens is discussed and it is suggested that the presence of the HLA antigens associated with MS confers a specific disadvantage on individuals in the ability to handle infection by the MS causative agent and that this allows damaging immunological processes to develop.