Background: Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) have been used to define a novel class of CNS demyelinating disorders. In adults, these disorders mainly affect the optic nerve and spinal cord, with approximately 50% of patients relapsing. Currently, there is no method of predicting relapse. Objective: We aimed to identify the prognostic utility of two key MOG antibody epitopes, Proline42 (P42) and Histidine103/Serine104 (H103/S104), in predicting a relapsing disease course. Methods: A flow cytometry live cell-based assay was utilised to determine the level of antibody binding to wild-type MOG as well as two mutants of MOG, P42S and H103A/S104E, in 306 MOG antibody-positive adults. Clinical information including lesion localisation and disease course were collected from 177 of these patients. Results: Of the patients who bound to a non-P42 epitope, 72% exhibited a relapsing disease course. This was enriched in patients with unilateral optic neuritis (UON), where 94% of non-P42 patients relapsed. This is notable as UON patients account for a third of patients with a relapsing course in our cohort. In contrast, preliminary evidence suggests that for patients with transverse myelitis, a non-H103/S104 epitope may help predict a relapsing course. Conclusion: Our research supports the prognostic utility of MOG antibody epitopes in predicting a relapsing course, which will enable clinicians to modify treatment in susceptible patients.