Multiple sclerosis (MS), systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) are chronic, immune-mediated, relapsing-remitting disorders affecting young adults, the pathogenesis of which is still largely unknown. Neurological manifestations and magnetic resonance imaging (MRI) can be indistinguishable and there are no specific diagnostic tools. Treatment and prognosis are quite different. There is controversy about the prevalence and significance of antiphospholipid antibodies (aPL) in MS. A significant number of patients with APS/SLE are misdiagnosed as MS but evidence suggests they are distinct nosological entities. However, it is essential to differentiate them since APS may be responsive to anticoagulation. When assessing MS patients, clinicians should consider APS/SLE, especially if the MS has atypical features. A trial of anticoagulation might be worthwhile in some patients with atypical MS and consistently positive aPL.