A pathogenic role for circulating anti-myelin antibodies is difficult to establish in multiple sclerosis (MS). Here, we unravel a broad heterogeneity within the anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in humans and non-human primates, and demonstrate that detection of important epitopes of MOG within the pathogenic repertoire is exclusively dependent on presentation on a solid-phase MOG conformer. Results of ELISA and those of a liquid-phase assay were compared using a MOG protein with identical sequence but different conformations. We tested sera from 50 human subjects, plasma of Callithrix jacchus marmosets known to contain antibodies reactive to either conformational or linearized MOG, and monoclonal, conformation-dependent anti-MOG antibodies. We have found no antibody reactivity against the soluble MOG conformer in human serum, and show that this lack of detection is not due to technical artifacts. Rather, dominant epitopes of MOG are not displayed in soluble phase, as shown by a complete lack of binding of conformation-dependent mAb. In MP4-immune marmosets that exhibit demyelinating pathology due to spreading of antibody determinants to myelin-embedded MOG, only ELISA can detect pathogenic circulating anti-MOG antibodies. Thus, the accurate detection of important subsets of pathogenic anti-MOG antibodies requires methods in which MOG is displayed similarly to its natural conformation in myelin.