Objective: To investigate associations between cerebrovascular risk factors and anticardiolipin (aCL) immunoreactivity. Background: High titers of aCL immunoreactivity, mainly the immunoglobulin (Ig) G isotype, were shown to predict aCL-related thrombo-occlusive complications. Methods: aCL antibodies, and IgG and IgM isotypes were measured by a validated assay in a single laboratory, run in duplicate, in 749 individuals with first ischemic stroke (n = 300) and patients with other CNS disease or undergoing diagnostic procedures. Results: Age varied according to aCL categories, with a mean of 61.8 years among patients with negative aCL (<10 IgG phospholipid units [GPL]) to 02.3, 64.9, and 69.9 years in patients with immunoreactivity 10 to 20, 20 to 40, and >40 GPL respectively (p = 0.02). History of atrial fibrillation, congestive heart failure, or valvular heart disease was associated with significantly higher rates of positive IgG aCL (>10 GPL) and with higher immunoreactivity. IgG aCL immunoreactivity increased significantly, in a dose-response manner, as a function of the number of cerebrovascular risk factors present. In patients with first ischemic stroke, rates of 10 to 20, 20 to 40, and >40 GPL were 14%, 7%, and 0% among those with no risk factors versus 20%, 12%, and 12% respectively among patients with four or more risk factors (p = 0.007). No significant associations were identified, however, between IgM isotype aCL and any of the risk factors or increasing number of risk factors. Conclusion: The presence of multiple cerebrovascular risk factors is associated with substantially higher rates of positive IgG isotype aCL, and with higher immunoreactivity. These findings should caution against overdiagnosis of the antiphospholipid syndrome, and consequent changes in management among patients with multiple cerebrovascular risk factors.