Despite the definition of specific diagnostic criteria to identify radiologically isolated syndrome (RIS) suggestive of multiple sclerosis, its natural history remains incompletely understood. We retrospectively analyzed a Brazilian cohort of 12 patients to clarify their features and to emphasize the role of imaging predictors in clinical conversion. We demonstrated that, although some individuals did not exhibit progression over a lengthy follow-up period (16.7%), most patients will progress clinically or radiologically in the initial years of the follow-up (83.3%). Infratentorial and spinal cord involvement, as well as the total number of lesions, were more relevant predictors of progression than gadolinium enhancement. Further studies remain necessary to define the risk of conversion in males and to clarify the cognitive abilities of RIS patients. This study may provide an improved understanding of the natural course and evolution of incidental magnetic resonance imaging lesions, and further assists with the management of RIS in clinical practice.