The purpose of the present prospective observational study was to assess whether or not the presence of anticardiolipin antibodies (aCL) in unselected first ischemic stroke patients is associated with adverse outcome. Consecutive patients (n = 300; mean age 64 years; 48% males) presenting with a first acute ischemic stroke were evaluated for IgG aCL and were systematically followed up. During a median follow-up of 21 months, 58 patients (19%) died. Mortality rates were higher in patients with aCL >20 IgG phospholipid units (GPL) [33 vs. 18%; relative risk (RR) 1.94, 95% confidence interval (CI) 1.02–3.67; p = 0.042] or >40 GPL (40 vs. 19%; RR 2.46, 95% CI 1.05–5.75; p = 0.037). Elevated aCL did not confer an increased risk during follow-up of a combined end point of stroke, myocardial infarction and vascular death or of nonfatal thrombo-occlusive events. Rates of malignancy detected during follow-up were higher among patients with aCL >20 GPL (19 vs. 5%, p = 0.007) and >40 GPL (27 vs. 6%, p = 0.01). The excess mortality associated with elevated aCL was eliminated after adjustment for age, cardiovascular risk factors and malignancy. These results demonstrate that aCL above 20–40 GPL among consecutive ischemic stroke patients is a marker of increased mortality during follow-up, but older age and higher rates of cardiovascular risk factors and malignancy detected during follow-up account for the higher mortality.