A previous study has demonstrated that tilapia able to exhibit hyperlipidemia and hypercholesterolemia is a good model for the evaluation of beneficial effects of nutraceuticals. In this study, tilapia were used to evaluate the in vitro and in vivo effects of a hot water extract (FC-HW) of freshwater clam (Corbicula fluminea). FC-HW prolonged the lag phase of Cu(2+)-induced human and tilapia LDL oxidation. The prolongation of the lag phase was concentration-dependent in human (r(2)= 0.94) and tilapia LDL (r(2)= 0.98). The antioxidative potential of FC-HW was 0.33% (on a weight basis) of Trolox, a positive control. Male tilapia (n= 24) were randomly divided into 2 groups and separately fed for 60 d with an isocaloric also isoprotein diet containing 2% (w/w) FC-HW or a control diet. Body length and body mass were significantly higher in fish fed FC-HW than those of the control group (P < 0.05). Total triacylglycerol, cholesterol, and LDL-C in plasma of the FC-HW group were significantly lower (-89.9%, -61.8%, and -54.5%, respectively), while plasma total antioxidant capacity of the FC-HW group was higher and the lag phase in Cu(2+)-induced LDL oxidation was longer than those of the control group (P < 0.05). FC-HW demonstrated hypolipidemia and hypocholesterolemia effects and inhibited human LDL oxidation in vitro and tilapia LDL both in vitro and ex vivo, indicative that FC-HW can be a potential nutraceutical to reduce the risk factors of atherosclerosis.