Paraoxonase, a group of anti-oxidant serum enzymes associated with high-density lipoproteins (HDL), prevents the formation of - and inactivates - oxidized low-density lipoprotein (LDL) lipids. Increasing paraoxonase activity may contribute to the cardiovascular benefits of exercise and niacin therapy we have previously reported for men with metabolic syndrome (MetS) [MSSE Vol 39(5): #2478, 2007 and Vol 41(5): #3363, 2009]. PURPOSE: Our purpose was to characterize changes in paraoxonase concentration and activity after single aerobic exercise sessions conducted before and after 6 wks of niacin therapy in men with MetS. METHODS: Thirteen men (44 + 7 yrs; BMI = 34.5 + 3.4 kg·m²; % fat = 35 + 5; VO2max = 27.7 + 5.1 mL·min^-1·kg^-1; waist circumference = 108.8 + 8.2 cm; HDL-C = 39 + 8 and triglycerides = 287 + 96 mg/dL; HOMA score = 4.4 + 2.0) expended 500 kcals by treadmill walking at 65% of VO2max before and after a 6-wk regimen of prescription niacin. Niacin doses were titrated by 500 mg/wk from 500 to 1500 mg/dy and maintained at 1500 mg/dy for the last 4 wks. Fasting blood samples were collected before and 24 hr after each exercise session and analyzed for activities of paranoxonase (PONa), myeloperoxidase (MPOa), apolipoprotein A1 (Apo-A1), paranoxonase-1 (PON1) and oxidized LDL (oxLDL) concentrations and NMR analyses of lipoprotein characteristics. RESULTS: PONa, PON1, MPOa and oxLDL were unaltered after six weeks of niacin therapy and after exercise before undergoing niacin therapy (p > 0.05 for all). PON1 concentrations increased 12.3% (from 109.5 + 24.3 to 123.0 + 19.8 ug/ml) with the combination of niacin and exercise (p = 0.0145). The change in PON1 concentration was correlated with the change in small HDL particle number and Apo-A1 concentration with niacin and exercise. The change in PON1 was correlated with changes in LDL particle numbers after niacin therapy but not with niacin and exercise. The change in PONa was correlated with changes in large and medium HDL particle numbers and with changes in oxLDL and MPOa with niacin and exercise. CONCLUSIONS: The combination of niacin and exercise therapy in men with MetS include a modest increase in PON1 without observed changes in oxLDL or MPOa.