BACKGROUND: Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) is a predictor of cardiovascular events that has been shown to vary with race. The objective of this study was to examine factors associated with this racial variation. METHODS: We measured Lp-PLA(2) mass and activity in 714 healthy older adults with no clinical coronary heart disease and not taking dyslipidemia medication. We evaluated the association between race and Lp-PLA(2) mass and activity levels after adjustment for various covariates using multivariable linear regression. These covariates included age, sex, diabetes, hypertension, body mass index, lipid measurements, C-reactive protein, smoking status, physical activity, diet, income, and education level. We further examined genetic covariates that included three single nucleotide polymorphisms shown to be associated with Lp-PLA(2) activity levels. RESULTS: The mean age was 66 years. Whites had the highest Lp-PLA(2) mass and activity levels, followed by Hispanics and Asians, and then African-Americans; in age and sex adjusted analyses, these differences were significant for each non-White race as compared to Whites (p < 0.0001). For example, African-Americans were predicted to have a 55.0 ng/ml lower Lp-PLA(2) mass and 24.7 nmol/ml-min lower activity, compared with Whites, independent of age and sex (p < 0.0001). After adjustment for all covariates, race remained significantly correlated with Lp-PLA(2) mass and activity levels (p < 0.001) with African-Americans having 44.8 ng/ml lower Lp-PLA(2) mass and 17.3 nmol/ml-min lower activity compared with Whites (p < 0.0001). CONCLUSION: Biological, lifestyle, demographic, and select genetic factors do not appear to explain variations in Lp-PLA(2) mass and activity levels between Whites and non-Whites, suggesting that Lp-PLA(2) mass and activity levels may need to be interpreted differently for various races.