SummaryThe association of polyphenol content of human diet with low-grade inflammation is not yet fully understood. It was the objective of this study to evaluate the association of flavonoid and lignan intake with frequently used and easily applicable in clinical practice low-grade inflammation biomarkers, in a novel holistic approach. A total of 5,948 women and 5,965 men (aged ≥ 35years) were analysed from the Moli-sani cohort, randomly recruited from the general population. The EPIC-FFQ was used for dietary assessment. Flavonol, flavone, flavanone, flavanol, anthocyanin, isoflavone and lignan intakes were calculated using Eurofir eBASIS and the polyphenol antioxidant content (PAC)-score was constructed to assess the total content of diet in these nutrients. CRP levels, WBC and PLT count and granulocyte to lymphocyte ratio were conceived as low-grade inflammation biomarkers. INFLA-score was constructed summarizing synergistic effects of these biomarkers. The INFLA-score was negatively associated with PAC-score in different levels of adjustment, in both genders (for all β-coef< 0, P< 0.05). 10 units increase in PAC-score was associated with 5–8 % decrease in the likelihood of higher low-grade inflammation status (i. e. higher quartile of INFLA-score) in men and women (odds ratio [ORs] 0.92 to 0.95, p< 0.05). The total variation of INFLA-score that was explained by PAC-score was estimated to be 16.7 % in women and 9.1 % in men (%R2=16.7 and 9.1). In conclusion, polyphenol content of diet evaluated in a holistic approach was negatively associated with a score of low-grade inflammation biomarkers in a large population based study. For the first time low-grade inflammation was evaluated in a holistic way through INFLA-score and was associated with polyphenol content of diet.Supplementary Material to this article is available online at www.thrombosis-online.com.