Abstract Background No intervention follow-up study has examined the association between plasma n-6 polyunsaturated fatty acids (PUFAs) and lipoprotein-associated phospholipase A2 (Lp-PLA2), which is a risk factor for cardiovascular disease (CVD). We aimed to determine whether the administration of linoleic acid (LA, 18:2n-6) in soy oil affected Lp-PLA2 activity in healthy adults. Methods Self-reported healthy participants (n = 150) were randomly assigned to three groups: a low LA group, in which 10 mL soy oil was replaced with one apple; a medium LA group, in which the typical food intake was maintained; and a high LA group, in which 1/3 cup of cooked refined rice was replaced with 9.9 g of soy oil capsules daily. Plasma fatty acids and Lp-PLA2 activity were measured along with other CVD risk factors. Results After 8 weeks of treatment, plasma LA levels decreased in the low LA group and increased in the high LA group. The high LA group showed greater increases in apolipoprotein B (apoB) and oxidized low-density lipoprotein (ox-LDL) than those in the low LA group. Plasma LA levels and Lp-PLA2 activities demonstrated greater increases in the high LA group than those in the medium and low LA groups. Changes in plasma LA positively and independently correlated with changes in Lp-PLA2 activity, which was negatively correlated with changes in collagen-epinephrine closure time (CEPI-CT). Conclusions An increase in plasma LA following intake of soy oil was independently associated with Lp-PLA2 activity, which was also related to apoB, ox-LDL and CEPI-CT. Trial registration ClinicalTrail.gov Identifier: NCT02753907 , registered 25 April 2016 (retrospectively registered).