Background and Purpose-Inflammation plays a critical role in the development of vascular disease, and increased levels of the inflammatory biomarkers, lipoprotein-associated phospholipase A 2 (Lp-PLA 2), and high-sensitivity C-reactive protein (hs-CRP) have been shown to be associated with an increased risk for ischemic stroke. Methods-In a prospective case-cohort (n = 949) study in 12 762 apparently healthy, middle-aged men and women in the Atherosclerosis Risk in Communities (ARIC) study, we first examined whether Lp-PLA 2 and hs-CRP levels improved the area under the receiver operator characteristic curve (AUC) for 5-year ischemic stroke risk. We then examined how Lp-PLA 2 and hs-CRP levels altered classification of individuals into low-, intermediate-, or high-risk categories compared with traditional risk factors. Results-In a model using traditional risk factors alone, the AUC adjusted for optimism was 0.732, whereas adding hs-CRP improved the AUC to 0.743, and adding Lp-PLA 2 significantly improved the AUC to 0.752. Addition of hs-CRP and Lp-PLA 2 together in the model improved the AUC to 0.761, and the addition of the interaction between Lp-PLA 2 and hs-CRP further significantly improved the AUC to 0.774. With the use of traditional risk factors to assess 5-year risk for ischemic stroke, 86% of participants were categorized as low risk (<2%);11%, intermediate risk (2% to 5%);and 3%, high risk (>5%). The addition of hs-CRP, Lp-PLA 2, and their interaction to the model reclassified 4%, 39%, and 34% of the low-, intermediate-and high-risk categories, respectively. Conclusion-Lp-PLA 2 and hs-CRP may be useful in individuals classified as intermediate risk for ischemic stroke by traditional risk factors.