We report a case of a 25-year-old woman presenting with a 6 month history of REM sleep behavior disorder (RBD), confirmed by video-polysomnography. A brain MRI disclosed multiple cerebral periventricular and pontine non-gadolinium-enhancing hyperintensities and CSF isoelectric focusing showed oligoclonal bands, consistent with a diagnosis of probable multiple sclerosis (MS). RBD episodes disappeared after ACTH treatment, but clinical relapses and MRI follow-up confirmed the diagnosis of MS. Although RBD has been described in association with MS, it has not been reported as a heralding sign, nor related to MS brainstem lesion. Our case emphasizes the value of RBD as a clinical tell-tale sign: when isolated RBD appears in a young subject, brain-imaging studies and long-term follow-up are warranted.