Controversy remains regarding whether there is an association between circulating lipoprotein-associated phospholipase A2 (Lp-PLA2), cytokines, and oxidative stress in healthy postmenopausal women. We investigated the influence of age on Lp-PLA2 activity in postmenopausal women not using hormone therapy and the relationship of Lp-PLA2 enzyme activity to serum cytokine levels and oxidative stress indices. Normal weight (n = 1284) and overweight/obese (n = 707) postmenopausal women not using hormone therapy were categorized into five age groups: 50-54, 55-59, 60-64, 65-69, and 70-89 years. Overweight-obese women showed higher plasma Lp-PLA2 activity, urinary 8-epi-prostaglandin F2α (8-epi-PGF2α), serum interleukin (IL)-6, and smaller LDL particles than normal-weight women after adjusting for age, years postmenopause, smoking, drinking, blood pressure, glucose, insulin, lipid profiles, BMI, and waist circumference. Overweight/obese women 70-89 years old showed higher Lp-PLA2 activity than those aged 50-54 years, whereas no significant difference in Lp-PLA2 activity existed across normal-weight female age groups. Overweight/obese women aged ≥ 65 years showed higher Lp-PLA2, oxidized LDL (ox-LDL), IL-6, and 8-epi-PGF2α than age-matched normal-weight controls. Overweight/obese women aged ≥ 70 years had higher ox-LDL levels than those aged 50-59, and overweight/obese women aged 65-89 showed higher IL-6 and 8-epi-PGF2α. There were strong positive correlations between Lp-PLA2 and ox-LDL (r = 0.385, P < 0.001), Lp-PLA2 and IL-6 (r = 0.293, P < 0.001), and ox-LDL and IL-6 (r = 0.303, P < 0.001) in overweight/obese women; however, these relationships were weak in normal-weight women. These results suggest that aging and obesity-related oxidative and inflammatory mediators are associated with Lp-PLA2 activity in overweight/obese postmenopausal women not using hormone therapy.