OBJECTIVES: We studied the association of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) mass and activity with various lifestyle, clinical and biochemical characteristics in cardiovascular disease (CVD) free adults. BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a novel biomarker of inflammation and risk for CVD. The Lp-PLA(2) mass and activity are primarily influenced by the plasma levels of low-density lipoprotein (LDL), however the influence of various lifestyle characteristics on Lp-PLA(2) have not been adequately studied. METHODS AND RESULTS: In a random sub-sample of 186 subjects, 64 men (52+/-13 years) and 122 women (48+/-13 years) from the ATTICA Study (Greece), Lp-PLA(2) activity and mass in total plasma as well as the enzyme activity and mass associated with high-density lipoprotein (HDL-Lp-PLA(2)) were determined using established methods. Several socio-demographic, lifestyle, clinical and biochemical parameters were assessed in all participants. Multiple linear regression analysis revealed that among the lifestyle characteristics, total plasma Lp-PLA(2) activity and mass were positively and independently associated with current smoking (p=0.02 and p=0.05, respectively), as well as with exposure to second-hand smoke (p=0.02 and p=0.01, respectively). Furthermore, HDL-Lp-PLA(2) activity and mass were inversely and independently associated with current smoking (p=0.04 and p=0.09, respectively). CONCLUSIONS: Smoking is associated with and might even induce an increase in proatherogenic total plasma Lp-PLA(2), but attenuates antiatherogenic HDL-Lp-PLA(2). These results further support the role of smoking as an important avoidable cause of CVD.