OBJECTIVE To estimate the association between plasma lipoprotein-associated phospholipase A2 (Lp-PLA2 ) levels and cardiovascular disease (CVD). METHODS We searched MEDLINE (January 1, 1985, through September 30, 2006), the Cochrane library (from inception through 2006), conference proceedings, and reference sections of obtained articles and contacted experts for unpublished studies. Eligible studies were cohorts with 1 year or more of follow-up or case-control designs that provided risk estimates for CVD according to blood levels of Lp-PLA2 that were unadjusted or adjusted for conventional CVD risk factors. We used random-effects meta-analysis to estimate the association between Lp-PLA2 and CVD risk and conducted preplanned subgroup analyses to identify risk-subgroup interactions that could explain between-study differences. RESULTS We found 14 eligible studies (N=20,549 patients) that reported either Lp-PLA2 plasma activity (n=5) or an immunoassay that measured the plasma concentration (n=9). The meta-analytic estimate from the unadjusted odds ratio for the association between elevated Lp-PLA2 levels and CVD risk was 1.51 (95% confidence interval, 1.30-1.75) and from the odds ratio adjusted for conventional CVD risk factors was 1.60 (95% confidence interval, 1.36-1.89). Differences in study methods explained differences in results across studies. CONCLUSIONS Lipoprotein-associated phospholipase A2 is significantly associated with CVD. The risk estimate appears to be relatively unaffected by adjustment for conventional CVD risk factors. Measurement of Lp-PLA2 may be useful in CVD risk stratification. In addition, Lp-PLA2 may represent a potential therapeutic target for CVD risk reduction.