METHODS: We determined the effect of smoking on PON1 activity levels in a population-based sample of 1380 subjects and examined the possibility of regular physical activity modulating the effect of cigarette smoking on PON1 activity levels at a population level. RESULTS: Mean PON1 activity was significantly lower in smokers than in non- or ex-smokers (237.6+/-8.4 vs. 276.7+/-5.3 U/l, mean+/-S.E.M.; P= 0.001). PON1 activity levels were significantly higher in physically active subjects than in those who were inactive (296.1+/-10.4 vs. 260.1+/-9.2 U/l; P=0.002). Inactive smokers showed significantly lower PON1 activity levels than inactive nonsmokers (P=0.002). These differences disappeared when active nonsmokers were compared with active smokers. Serum PON1 activity levels were found to be significantly increased in active smokers compared to those in inactive smokers. A statistically significant interaction (P=0.003) between smoking and physical activity on PON1 activity was observed. CONCLUSION: Smoking appears to have a deleterious effect on PON1 activity levels. Being physically active clearly attenuates this effect.