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Background: The extent to which omega-3 fatty acid (FA) status is related to risk for death from any cause and for incident cardiovascular disease (CVD) remains controversial.Objective: To examine this association in the Framingham Heart Study (FHS).Design: Prospective and observational.Setting: FHS Offspring cohort.Measurements: The primary exposure marker was red blood cell (RBC) levels of eicosapentaenoic and docosahexaenoic acids (EPA and DHA; the Omega-3 Index) which was measured at baseline. Secondary markers included RBC EPA, DHA, alpha-linolenic and docosapentaenoic (n-3) acids. Outcomes included mortality (total, CVD, cancer, and other) and total CVD events. Median follow-up was 7.3 years. Cox proportional hazards models were adjusted for 18 demographic characteristics, clinical status, therapies and other CVD risk factors including C-reactive protein levels.Results: Among the 2500 participants (mean age 66 years, 54% women; all free of CVD at baseline) there were 350 deaths (58 from CVD, 146 from cancer, 128 from other known causes, and 18 from unknown causes). There were 245 CVD events. In multivariable-adjusted analyses, a higher Omega-3 Index was associated with significantly lower risks (p-values for trends across quintiles) for total mortality (p=0.02) and non-CVD, non-cancer mortality (p = 0.009; Figure), and for total CVD events (p=0.008). Those in the highest versus the lowest Omega-3 Index quintiles (i.e., >6.8% vs. <4.2%) had a 34% lower risk for death from any cause and a 39% lower risk for incident CVD. Associations were generally stronger for DHA than for EPA. When total cholesterol was compared with the Omega-3 Index in the same models, the latter was significantly related with these outcomes, but the former was not. Substituting the omega-6:omega-3 ratio for the Omega-3 Index did not alter the outcomes.Limitations: Relatively short follow-up time and a single exposure assessment.Conclusions: A higher Omega-3 Index was associated with reduced risk of both CVD and all-cause mortality.