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Background: Although the Healthy Eating Index (HEI) is widely recommended to reduce the risk of cardiovascular disease and all-cause death, there are significant differences in physiological and nutritional factors between the sexes. The potential impact of sex on adult dietary health is still poorly understood. The study was designed to assess whether the health benefits of diet differed by sex., Methods: In a prospective study of 39,567 U.S. adults (51.2% female, age 46.8 ± 17.6 years), we examined sex-specific, multivariable-adjusted associations of HEI with all-cause mortality and cardiovascular disease mortality. Restricted cubic splines (RCS), subgroup analysis, propensity score matching (PSM), random forest feature importance, and sensitivity analysis were also used., Results: During 328,403 person-years of follow-up, a total of 4754 all-cause deaths were recorded, including 1481 cardiovascular deaths. Compared to the lowest quartile of HEI, the all-cause mortality rate of females and males in the highest quartile array decreased by 34% (HR 0.66 [95% CI 0.55-0.8]) and 15% (HR 0.85 [95% CI 0.73-0.99]), respectively. The restricted cubic spline showed a linear inverse association between baseline HEI and all-cause mortality and CVD mortality, with similar sex-specific results. Similarly, component scores were sex-specific for mortality risk, with females benefiting more from diet. The benefits of dairy products, vegetables, and sodium scores on the risk of all-cause death were higher in males and females. However, the benefits of vegetable, sodium, and fatty acid scores on the risk of cardiovascular death were different., Conclusions: In the adult population of the U.S., there are more opportunities for females to reduce the risk of all-cause mortality and cardiovascular mortality from the same dose of healthy dietary intake than males. These findings could reduce the risk of death by motivating the population, especially females, to consume healthy dietary components, especially vegetables and dairy products., (© 2024. The Author(s).)