Epidemiological studies strongly support the role of procyanidin-rich beverages and fruit in the prevention of cardiovascular diseases. Procyanidins extracted from the litchi pericarp (LPPC), a new source of procyanidins, were isolated and identified in our laboratory and have been proven to possess strong antioxidant activity in vitro. In the present study, we investigated the anti-atherosclerotic effects of LPPC in apolipoprotein E knockout (ApoE KO) mice fed a high fat diet for 24 weeks. LPPC (100 mg kg-1 body mass daily) significantly reduced the atherosclerotic lesion size (P < 0.01 versus ApoE KO mice), excess NO production and iNOS expression. Moreover, the mRNA and protein expressions of eNOS in the aortas of ApoE KO mice were increased by LPPC which further explains the endothelial protective action of LPPC. LPPC also showed profound antioxidant effects in ApoE KO mice. Plasma TBARS contents and the mRNA expression for NADPH oxidase (p47phox, p67phox, NOX-2/gp91phox and NOX-4) in the aortas of ApoE KO mice were significantly reduced, whereas plasma SOD activity was markedly elevated by LPPC. These results elucidated that LPPC could ameliorate atherosclerosis in ApoE-KO mice by improving NO bioavailability and reducing oxidative stress through NADPH oxidase-dependent mechanisms.