Growing evidence suggests that the effects of diet on cardiovascular disease (CVD) occur through mechanisms involving subclinical inflammation. We assessed whether reported dietary fatty acid intake correlates with a serum high-sensitivity C-reactive protein (hs-CRP) concentration in a population-based sample of US men and women.In this cross-sectional analysis, participants were selected from the US National Health and Nutrition Examination Survey (NHANES) and restricted to those with available data on dietary intake, biochemical and anthropometric measurements from 2001 to 2010. All statistical analyses accounted for the survey design and sample weights by using SPSS Complex Samples v22.0 (IBM Corp, Armonk, NY).Of the 17,689 participants analyzed, 8607 (48.3%) were men. The mean age was 45.8 years in the overall sample, 44.9 years in men, and 46.5 years in women (P = 0.047). The age-, race-, and sex-adjusted mean dietary intakes of total polyunsaturated fatty acids (PUFAs), PUFAs 18:2 (octadecadienoic), and PUFAs 18:3 (octadecatrienoic) monotonically decreased across hs-CRP quartiles (P < 0.001), whereas dietary cholesterol increased across hs-CRP quartiles (P < 0.001)This study provides further evidence of an association between fatty acid intake and subclinical inflammation markers. hs-CRP concentrations are likely modulated by dietary fatty acid intake. However, the causality of this association needs to be demonstrated in clinical trials.