Background and Purpose: The association between anticardiolipin antibody (aCL) and ischemic stroke is controversial, and there are few case-control studies of Asian populations. The aim of this study, therefore, was to determine whether aCL is an independent risk factor for ischemic stroke in Taiwanese patients over the age of 40 years. Methods: Both the IgG and IgM isotypes of aCL were measured in 273 patients (>40 years of age) hospitalized for first-ever ischemic stroke and in 181 non-stroke controls. Results were defined as: negative (<10 IgG phospholipid units [GPL] or <7.5 IgM phospholipid units [MPL]); low positive (10–20 GPL or 7.5–15 MPL); or, high positive (>20 GPL or >15 MPL). Odds ratios (OR) were estimated by logistic regression with adjustment for potential confounders. Results: A high positive IgG aCL was present in 4.4% of the stroke patients and 1.2% of the controls. Age- and sex-adjusted analysis showed a borderline association between a high positive level for aCL IgG titer and stroke, with an OR of 4.01 (95% CI 0.87–18.37; p = 0.0739). Final analysis, with adjustments for age, sex, hypertension, diabetes, tobacco smoking, atrial fibrillation, left ventricular hypertrophy and hyperlipidemia, revealed an OR of 5.25 (95% CI 1.06–25.89; p = 0.0419). Conclusions: The results of this study suggest that elevated titer of aCL IgG (>20 GPL) is associated with first-ever ischemic stroke in Taiwanese patients aged over 40 years. High positive aCL titer is related to ischemic stroke after adjustment for conventional cerebrovascular risk factors, indicating that it is probably an independent risk factor for ischemic stroke.