Hughes (antiphospholipid) syndrome (APS) can mimic multiple sclerosis (MS). We analyzed the clinical, laboratory, and imaging findings of MS-like expression in a cohort of patients with APS in an attempt to identify parameters that might differentiate the 2 entities. We studied 27 patients who were referred to our unit with the diagnosis of probable or definite MS made by a neurologist. All patients were referred to our lupus clinic because of symptoms suggesting an underlying connective tissue disease, uncommon findings for MS on magnetic resonance imaging (MRI), atypical evolution of MS, or antiphospholipid antibody (aPL) positivity. aPL, antinuclear antibody (ANA), anti-dsDNA, and anti-extractable nuclear antigen (ENA) antibodies were measured by standard methods. MRI was performed in every patient and compared with MRI of 25 definite MS patients who did not have aPL. An index severity score was calculated based on the size and number of increased signal intensity areas in MRI. In the past medical history, 8 patients with primary APS and 6 with APS secondary to systemic lupus erythematosus (SLE) had had symptoms related to these conditions. Neurologic symptoms and physical examination of the patients were not different from those common in MS patients. Laboratory findings were not a useful tool to distinguish APS from MS. When MRI from APS patients was compared globally with MRI from MS patients, MS patients had significantly increased severity score in white matter (p < 0.001), cerebellum (p = 0.035), pons (p < 0.015), and when all areas were taken together (p < 0.001). Patients with APS had significantly increased scores in the putamen (p < 0.01). No differences were noticed in the degree of atrophy. When taken individually, MRI from APS patients could not be distinguished from MRI from MS patients. Most of the patients with primary APS showed a good response to oral anticoagulant treatment. In patients with secondary APS, the outcome was poorer. Hughes syndrome (APS) and MS can be difficult to distinguish. A careful medical history, a previous history of thrombosis and/or fetal loss, an abnormal localization of the lesions in MRI, and the response to anticoagulant therapy might be helpful in the differential diagnosis. We believe that testing for aPL should become routine in all patients with MS.