Better understanding of factors contributing to inter-individual variability in biomarkers of vitamin K could enhance the understanding of the equivocal role of vitamin K in cardiovascular disease. Based on the known biology of phylloquinone, the major form of vitamin K, we hypothesized that plasma lipids contribute to the variable response of biomarkers of vitamin K metabolism to phylloquinone supplementation.We examined the association of plasma lipids and 27 lipid-related genetic variants with the response of biomarkers of vitamin K metabolism in a secondary analysis of data from a 3-year phylloquinone supplementation trial in men (n=66) and women (n=85). Year 3 plasma triglycerides (TG), but not total cholesterol, LDL-cholesterol, or HDL-cholesterol, were associated with the plasma phylloquinone response (Men: β=1.01, p<0.001, R =0.34; Women: β=0.61, p=0.008, R =0.11; sex interaction p=0.077). Four variants and the TG-weighted genetic risk score were associated with the plasma phylloquinone response in men only. Plasma lipids were not associated with changes in biomarkers of vitamin K function (undercarboxylated osteocalcin and MGP) in either sex.Plasma TG were an important determinant of the inter-individual response of plasma phylloquinone to phylloquinone supplementation, but changes in biomarkers of vitamin K carboxylation were not influenced by lipids. This article is protected by copyright. All rights reserved.