BACKGROUND AND AIMS: To compare the effects of n-3 long chain polyunsaturated fatty acids (n-3 LCPUFA), with those of fenofibrate, on markers of inflammation and vascular function, and on the serum lipoprotein profile in overweight and obese subjects. METHODS AND RESULTS: Twenty overweight and obese subjects participated in a randomized, double-blind, placebo-controlled intervention trial and received 3.7 g/d n-3 fatty acids (providing 1.7 g/d EPA and 1.2 g/d DHA), 200 mg fenofibrate or placebo treatment for 6 weeks separated by a 2 weeks wash-out period. Fish oil and fenofibrate treatment reduced triglyceride (-0.61 +/- 0.81 mmol/L, P < 0.001, and -0.34 +/- 0.85 mmol/L, P = 0.048, respectively) and increased HDL cholesterol concentrations (0.13 +/- 0.21 mmol/L, P = 0.013, and 0.10 +/- 0.18 mmol/L, P = 0.076), as reflected by a decrease of large very VLDL particles and increases of large HDL particles and medium size HDL particles. Fish oil increased serum LDL cholesterol concentrations (0.34 +/- 0.59 mmol/L, P = 0.013). Fenofibrate reduced concentrations of soluble endothelial selectin (sE-selectin) (-4.1 +/- 7.5 ng/mL, P = 0.032), but increased those of macrophage chemoattractant protein 1 (MCP1) (28 +/- 55 ng/mL, P = 0.034). Fish oil had no effects on these markers. CONCLUSION: Although n-3 LCPUFA and fenofibrate can both activate PPARalpha, they have differential effects on cardiovascular risk markers. In overweight and obese subjects fenofibrate (200 mg/d) or n-3 LCPUFA (3.7 g/d) treatment for 6 weeks did not improve markers for low-grade systemic inflammation, while fenofibrate had more profound effects on plasma lipids and markers for vascular activity compared to fish oil. Registration number clinical trials EudraCT 2006-005743-28.