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The role of anticardiolipin antibodies (aCLs) as novel risk factors for ischemic stroke and transient ischemic attacks (TIAs) has been a matter of debate. Prior cohort studies included only selected subjects, mostly men. We related serum concentrations of aCLs to incident first ischemic stroke/TIA among men and women in the Framingham Heart Study cohort and offspring.There were a total of 2712 women (mean age, 59.3 years) and 2262 men (mean age, 58.3 years) free of stroke/TIA at the time of their baseline examinations. An enzyme immunoassay was used to measure aCLs. Optical density of the sample serum compared with the reference serum was defined as the aCL screening ratio (aCL SR). Analyses were based on sex-specific aCL SR quartiles and individual ratios.During the 11-year follow-up, 222 ischemic strokes/TIAs occurred. In multivariate analysis, after adjustment for age, prior cardiovascular disease, systolic blood pressure, diabetes, smoking, C-reactive protein, and total and high-density lipoprotein cholesterol levels, an aCL SR of >0.4 (78% of sample) was significantly associated with an increased risk of ischemic stroke/TIA for women (hazard ratio [HR], 2.6; 95% confidence interval [CI], 1.3 to 5.4; absolute risk, 3.2%, 95% CI, 2.2 to 4.3) but not in men (HR, 1.3; 95% CI, 0.7 to 2.4; absolute risk, 4.5%; 95% CI, 3.0 to 6.0). Similar results were obtained when the higher 3 aCL SR quartiles were compared with the lowest.Elevated serum concentrations of aCLs, independently of other cardiovascular risk factors, significantly predict the risk of future ischemic stroke and TIA in women but not in men.