Scope: Paraoxonase-1 (PON-1), associated with HDL, is regarded as anti-atherogenic, attributed to its ability to hydrolyze oxidized lipids. Here, the impact of PON and apolipoprotein E genotypes, age, alcohol and HDL-cholesterol (HDL-C) on PON activity is examined. Methods and results: In total, 104 healthy UK adults participated in the study, with basal (PONA) and stimulated (PONB) PON-1 activities and arylesterase activity determined in these individuals. In univariate and correlation analysis age, HDL-C, alcohol intake and both PON genotypes were significantly associated with PONA and PONB activities (p<0.05). However, in the standard linear regression model, which explained 69% of the variability in both PONA (p<0.001) and PONB activities (p<0.001) only PON Q192R genotype emerged as a significant independent determinant, with four to fivefold higher levels in the RR versus wild-type QQ genotype groups. For PON arylesterase, HDL-C (p=0.030), apolipoprotein E (p=0.023) and PON Q192R (p=0.002) and PON L55M (p=0.002) genotypes collectively explained 14% of the total variability in the regression model. Conclusion: Our results indicate that PON genotypes are stronger determinants of PON activity relative to the other potential modulators assessed. The relative impact of dietary components on PON activities remains to be established.