The lipoprotein-associated phospholipase A2 (Lp-PLA2) metabolizes oxidized phospholipids, generating lysophosphatidylcholine. The activity of the enzyme is known to be influenced largely by a single-nucleotide polymorphism, G994T, in the Lp-PLA2 gene. Interestingly, this polymorphism is much more prevalent in Japanese than Caucasians. The purpose of the current study was to evaluate the effects of the G994T, several environmental factors, and their interactions on the Lp-PLA2 activity in a large Japanese cohort. Participants (1,110 males and 908 females) of a health-screening examination were recruited for this study. Genotyping of the G994T was done using allele-specific polymerase chain reaction (PCR). The Lp-PLA2 activity was measured using commercial kits. The minor allele (994T) frequency of the polymorphism was 0.17 in this study, which was consistent with previous reports. According to the multivariate linear regression analysis, the G994T was the most potent factor influencing the enzyme activity (standardized = 0.