Chronic smoking is associated with endothelial dysfunction and inflammation, with oxidative stress contributing to both these processes. In this study, we investigated the effect of combined antioxidant treatment with Enzogenol, a flavonoid extract from the bark of Pinus radiata and vitamin C, over and above vitamin C alone, on endothelial function, plasma markers of inflammation and oxidative stress, blood pressure (BP) and anthropometrics. Forty-four chronic smokers without established cardiovascular disease were assigned randomly to receive either 480 mg Enzogenol and 60 mg vitamin C, or 60 mg vitamin C alone daily for 12 weeks. Endothelial function in the brachial artery was assessed by flow-mediated vasodilation (FMD). FMD improved in both treatment groups (p < 0.001), with no significant difference between the two groups (p = 0.84). In the group receiving Enzogenol and vitamin C, protein carbonyl levels were significantly reduced compared to the group taking vitamin C alone (p = 0.03). Enzogenol and vitamin C resulted in a significant reduction in fibrinogen levels in heavy smokers compared with vitamin C alone (p < 0.009). These findings demonstrated that co-supplementation with Enzogenol and vitamin C in smokers conferred no additional beneficial effect on macrovascular endothelial function over and above that seen in the vitamin C alone group. However, Enzogenol did demonstrate additional favourable effects on protein oxidative damage and fibrinogen levels.