Background: Risk factors of cardiovascular disease such as lipid aberrations, hypertension, abdominal adiposity and elevations in systemic inflammation, are prominent aetiologies in hyperlipidemia. Supplementation with n-3 PUFA is associated with a reduction in cardiovascular events through its hypotriglyceridemic, anti-aggregatory and anti-inflammatory properties. Plant sterols have potent hypocholesterolemic properties, although their effect on the inflammatory cascade is uncertain. This study investigated the effect of combined supplementation with n-3 PUFA and plant sterols on cardiovascular risk factors, blood pressure, body composition, markers of systemic inflammation and overall risk, in hyperlipidemic individuals. Methods: The study was a 3-week randomised, double-blind, placebo-controlled, 2 × 2 factorial design, in four parallel groups. Sixty hyperlipidemic participants were randomised to recieve either sunola oil or 1.4 g/d n-3 PUFA capsules with or without 2 g plant sterols per day. Results: The combination of n-3 PUFA and plant sterols reduced several inflammatory markers. High sensitivity C-reactive protein (hs-CRP) was reduced by 39% (P = 0.009), tumor necrosis factor-α (TNF-α) by 10% (P = 0.02), interleukin-6 (IL-6) by 10.7% (P = 0.009), leukotriene B₄ (LTB₄) by 29.5% (P = 0.01) and adiponectin was increased by 29.5% (P = 0.05). Overall cardiovascular risk was reduced by 22.6% (P = 0.006) in the combination group. Conclusion: We have demonstrated, for the first time that dietary intervention with n-3 PUFA and plant sterols reduces systemic inflammation in hyperlipidemic individuals. Furthermore, our results suggest that reducing inflammation provides a potential mechanism by which the combination of n-3 PUFA and plant sterols are cardioprotective.