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There is an association between anticardiolipin antibodies (aCL) and ischemic stroke. There are, however, also occasional reports linking aCL with other CNS diseases (OND), particularly with multiple sclerosis (MS). Hence, we studied the specificity of aCL for ischemic stroke.Prospective, consecutively identified patients evaluated for aCL (immunoglobulin G [IgG] and immunoglobulin M [IgM] isotypes) were divided into two groups: ischemic stroke (first ever) and OND (stroke-free subjects affected by OND).The ischemic stroke group (n = 300) and the OND (n = 149) differed in the following risk factors: age (64 ± 14 versus 58 ± 15 years; p < 0.001) and proportions of African Americans (67% versus 29%; p < 0.001); current cigarette smoker (26% versus 17%; p = 0.028); hypertensive (69% versus 34%; p < 0.001); diabetic (18% versus 7%; p = 0.001); history of angina (16% versus 8%; p = 0.015) or myocardial infarction (15% versus 3%; p < 0.001). There were higher rates of aCL positivity (26% versus 17%; p = 0.050), IgG-aCL > 10 GPL (23% versus 11%; p = 0.003) or IgG aCL > 20 GPL (12% versus 4%; p = 0.012) among the stroke group than among the OND group. No differences in IgG-aCL positivity were found between the MS group and the rest of the OND group but the MS patients had a higher rate of IgM-aCL positivity than the other OND patients.IgG-aCL positivity does not appear to be a marker for CNS disease generally but of ischemic stroke.