Background Atrial fibrillation is associated with increased stroke risk; available risk prediction tools have modest accuracy. We hypothesized that circulating stroke risk biomarkers may improve stroke risk prediction in atrial fibrillation. Methods and Results The REGARDS (Reasons for Geographic and Racial Differences in Stroke) study is a prospective cohort study of 30 239 Black and White adults age ≥45 years. A nested study of stroke cases and a random sample of the cohort included 175 participants (63% women, 37% Black adults) with baseline atrial fibrillation and available blood biomarker data. There were 81 ischemic strokes over 5.2 years in these participants. Adjusted for demographics, stroke risk factors, and warfarin use, the following biomarkers were associated with stroke risk (hazard ratio [HR]; 95% CI for upper versus lower tertile): cystatin C (3.16; 1.04–9.58), factor VIII antigen (2.77; 1.03–7.48), interleukin‐6 (9.35; 1.95–44.78), and NT‐proBNP (N‐terminal B‐type natriuretic peptide) (4.21; 1.24–14.29). A multimarker risk score based on the number of blood biomarkers in the highest tertile was developed; adjusted HRs of stroke for 1, 2, and 3+ elevated blood biomarkers, compared with none, were 1.75 (0.57–5.40), 4.97 (1.20–20.5), and 9.51 (2.22–40.8), respectively. Incorporating the multimarker risk score to the CHA ₂ DS ₂ VASc score resulted in a net reclassification improvement of 0.34 (95% CI, 0.04–0.65). Conclusions Findings in this biracial cohort suggested the possibility of substantial improvement in stroke risk prediction in atrial fibrillation using blood biomarkers or a multimarker risk score.