Introduction: Diets rich in plant-based foods have been associated with lower stroke risk. Plant-based foods contain a variety of potentially cardioprotective compounds, including flavonoids. We assessed the hypothesis that total flavonoid and flavonoid subclass intakes are associated with incident ischemic stroke in a population-based cohort oversampled for non-Hispanic blacks and Stroke Belt residents. Methods: Between 2003 and 2007, REGARDS enrolled black and white Americans age ≥ 45 years. Participants were 20,413 men and women who completed a Block 98 food frequency questionnaire (FFQ) and without stroke at baseline. Total flavonoid and flavonoid subclass (anthocyanidin, flavan-3-ol, flavanone, flavonol, flavone, proanthocyanidin and isoflavone) intakes were estimated using the food consumption reported by the FFQ and the flavonoid contents of each food using USDA databases. Incident strokes were captured by participant report and adjudicated by experts. Quintiles of flavonoid intake were examined as predictors of incident stroke using Cox regression models using the first quintile as the referent. Tests for trend used the quintile medians. Results: Adjusting for age and caloric intake, there was a statistically significant inverse association between total flavonoid intake and ischemic stroke (Q5 v Q1: HR=0.68; 95% CI=0.51, 0.90; p-trend=0.04) however, this association weakened after additional adjustment for demographic, socioeconomic and health behavior factors as well as self-reported CHD at baseline (Q5 v Q1: HR=0.77; 95% CI=0.58, 1.03; p-trend=0.31). A similar pattern was seen for flavanones (age, energy adjusted HR=0.74; 95% CI= 0.57, 0.95; p-trend=0.02; fully adjusted HR= 0.82; 95%CI=0.65, 1.05; p-trend=0.06). Effect estimates for total flavonoids, flavanones, proanthocyanidins, and isoflavones, suggested a protective, though nonlinear association with risk reduction emerging at the second quintile, though these did not achieve statistical significance (total flavonoids, fully adjusted HR (95% CI): Q2= 0.80 (0.61, 1.04); Q3= 0.85 (0.65, 1.11); Q4=0.92 (0.70, 1.19); Q5= 0.77 (0.58, 1.03)). Total flavonoid and flavanone intake were significantly associated with IS in fully adjusted models in women (total: Q5 v Q1 HR=0.62; 95% CI= 0.41, 0.94; p-trend=0.15; flavanones HR=0.65; 95% CI=0.44, 0.95; p-trend=0.03) but not in men (total: Q5 v Q1 HR=0.95; 95% CI= 0.63, 1.42; flavanones HR=0.80; 95% CI=0.58, 1.09; p-interaction=0.67). There was no effect modification by race or region of residence. Conclusion: Total dietary flavonoids and flavanones are associated with a reduction in risk of incident ischemic stroke, particularly in women. The emergence of a protective effect at the second quintile for total flavonoids, flavanones, proanthocyanidins and isoflavones is consistent with previous studies of dietary flavonoid intake and CVD mortality.