Background: Some previous prospective studies showed that dietary intake of ω3 polyunsaturated fatty acids was associated with lower risk of heart failure (HF), but no study has examined the association between plasma fatty acids and HF. Methods: We included 3,592 white participants from the Minneapolis field center of the Atherosclerosis Risk in Communities (ARIC) Study, aged 45 to 64 at baseline (1987-1989), initially free of coronary heart disease, stroke, and HF and who had cholesterol ester and phospholipid plasma fatty acids measured. Participants were followed through 2003, and incident HF was defined by a hospital discharge or death including a HF International Classification of Diseases code. Results: During the 14.3-year follow-up, we identified 197 cases of HF (110 for men and 87 for women). After adjustment for age and other confounders, higher saturated fatty acids, especially myristic (14:0) acid, were associated positively with incident HF in both men and women. Higher arachidonic (20:3,ω6) and long-chain ω3 polyunsaturated fatty acids, especially docosahexaenoic (22:6,ω3) acid, were associated inversely with HF in women but not in men. Neither plasma α-linolenic nor eicosapentaenoic acid was associated with incident HF. Conclusions: In both men and women, greater levels of saturated fatty acids may increase risk of HF. In women, arachidonic acid and long-chain ω3 polyunsaturated fatty acids may decrease risk of HF.