<i>Background and Objective:</i> The role of hemostatic factor levels in cerebral infarction remains uncertain. We studied the association of levels of several under-studied hemostatic factors with ischemic stroke in a population-based cohort. <i>Methods:</i> The Atherosclerosis Risk in Communities (ARIC) study includes 15,792 individuals aged 45–54 years at intake. Hemostatic factors II, V, IX, X, XI, XII, plasminogen and α₂-antiplasmin were measured on frozen citrate plasma samples from 1990 to 1992. A case-cohort design was used, including all incident ischemic strokes (n = 89) over a median of 7.5 years and a stratified cohort random sample (n = 412). To determine the association of hemostatic factors with incident ischemic stroke, we computed hazard ratios (HRs) using multivariate proportional hazard regression analyses adjusted for demographic and other cardiovascular risk factors. <i>Results:</i> The cohort random sample had a mean age (SD) of 56.9 (5.4) years and 42% were men. The age-, sex- and race-adjusted HRs for highest versus lowest quartiles were: factor XI (2.74, 95% CI 1.42–5.29), factor IX (1.92, 95% CI 0.99–3.73), and α₂-antiplasmin (2.24, 95% CI 1.16–4.33). Correspondingly, the HRs of ischemic stroke per SD increment of factors XI, IX, and α₂-antiplasmin were 1.64, 1.46 and 1.52, respectively (all p < 0.05). After multivariate adjustment including other clinical variables, the standardized HR remained significant for factor XI (1.50, 95% CI 1.10–2.05), but no other factor. <i>Conclusion:</i> A greater level of factor XI was associated with an increased risk of ischemic stroke. Higher factor XI levels might help identify patients at elevated ischemic stroke risk.