<b><i>Background:</i></b> The association of individual fatty acids with ischemic stroke has not been thoroughly studied, and results have been inconsistent. Few prospective studies have systematically explored the association of biomarkers of fatty acid intake with stroke. The aim of this study was<b> </b>to explore which individual plasma fatty acids would be associated with higher risk of ischemic stroke among whites. <b><i>Methods:</i></b> We studied 3,870 white men and women from the Minneapolis field center of the Atherosclerosis Risk in Communities (ARIC) Study, aged 45-64 years at baseline (1987-1989), who had plasma cholesterol ester (CE) and phospholipid (PL) fatty acids measured. Participants were followed through 2008 for incident ischemic stroke. Hazard ratios (HRs) with 95% confidence intervals (CIs) across quartiles of each fatty acid, measured as the percentage of total fatty acids, were calculated using the Cox proportional hazards model. <b><i>Results:</i></b> During a maximum of 22 years of follow-up, we identified 168 cases of ischemic stroke. After adjustment for age and sex, plasma levels of saturated fatty acids were associated positively: HR (95% CI) of the highest versus the lowest quartile for CE fraction was 1.93 (1.23-3.04, p for trend = 0.01) and that for PL fraction was 1.64 (1.05-2.57, p for trend = 0.03). There was also a positive linear association with monounsaturated fatty acids, especially with palmitoleic acid: HR (95% CI) of the highest versus the lowest quartile for CE fraction was 1.86 (1.20-2.87, p for trend = 0.003) and that for PL fraction was 1.52 (0.99-2.34, p for trend = 0.005). No associations of &#x03C9;-3 and &#x03C9;-6 polyunsaturated fatty acids with ischemic stroke were observed, but linoleic acid was inversely and nonlinearly associated with ischemic stroke: HR (95% CI) of the highest versus the lowest quartile for CE fraction was 0.64 (0.43-0.97, p for trend = 0.13) and that for PL fraction was 0.69 (0.45-1.05, p for trend = 0.24). These associations were generally unchanged after adjustment for cardiovascular risk factors. <b><i>Conclusions:</i></b> In this US cohort of whites, we found significant positive associations of plasma saturated and monounsaturated fatty acids, especially of palmitoleic acid, with ischemic stroke. We also found an inverse nonlinear association between linoleic acid and ischemic stroke.