Aim: The lipoprotein-associated phospholipase A2 (Lp-PLA(2)) level has been shown to be associated with the risk of clinical cardiovascular events. We aimed to investigate whether Lp-PLA(2) is associated with the progression of subclinical atherosclerosis in the general population. Methods: The degree of carotid plaque and the maximal intima-media thickness (IMT) were measured twice over a 5-year interval in 913 participants 45 to 74 years of age at baseline in a cohort study. The associations between the plasma Lp-PLA(2) activity and the progression of carotid plaque and changes in the IMT level were assessed according to sex after adjusting for traditional risk factors and the high-sensitivity C-reactive protein (hsCRP) level. Results: During the 5-year follow-up period, the progression of plaque was observed in 58.5% of men and 48.3% of women. The median maximal IMT level increased by 0.12 mm in men and 0.09 mm in women per year. The progression of plaque and changes in the IMT level increased according to the quartile of the Lp-PLA(2) activity in men (p<0.05 for trend), but not women. Following adjustment for traditional risk factors and the hsCRP level, the odds ratio for plaque progression associated with an increase in the Lp-PLA(2) activity of one standard deviation was 1.28 (95% CI=1.09-1.49, p=0.043) in men and 0.92 (95% CI=0.78-1.08, p=0.273) in women. The regression coefficient for IMT progression was 0.003 (p=0.004) in men and -0.001 (p=0.166) in women after adjusting for the other factors. Conclusions: The Lp-PLA(2) level is associated with the progression of subclinical atherosclerosis in men. Lp-PLA(2) may play an important role in the pathogenesis of atherosclerosis and be a potential target for the early prevention of cardiovascular disease.