The objective of this study was to investigate whether serum high-sensitivity C-reactive protein (hs-CRP) concentration varies with dietary fatty acid intake in Iranian adults free of any history of cardiovascular disease (CVD). This cross-sectional study involved 8105 adults (3142 men) aged 35-65 years. Dietary intake was assessed using 24-h dietary recalls. The relationship between anthropometric, cardiometabolic risk factors and dietary data and serum hs-CRP was assessed using SPSS software. Median crude dietary saturated fat decreased across hs-CRP quarters (P =0.009 for linear trend), whereas energy-adjusted total fat (P =0.017), trans-fat (P =0.016), monounsaturated fatty acids (P =0.030) and cholesterol (P =0.005) monotonically increased, with some evidence of statistical interactions by gender. In conclusion, serum hs-CRP concentrations were associated with some components of dietary fatty acid intake in our population of individuals without CVD, suggesting that dietary fat intake could be associated with subclinical inflammation.