Abstract: Strongylocentrotus nudus lipid composition is known but its biological effects are largely unknown. The anti-cancer effect of sea urchin lipids (SUL) and the underlying mechanism in a human hepatocellular carcinoma HepG2 cells were studied. The cell viability, apoptosis, mitochondrial transmembrane potential and reactive oxygen species (ROS) generation were studied. The protein levels of caspase-3, Bcl-2 and the mRNA levels of antioxidants including superoxide dismutase (SOD) and catalase (CAT) were also measured. The results showed that SUL treatment significantly inhibited the viability of HepG2 cells with reduced proliferation and elevated apoptosis as evidenced by the decreased Bcl-2 level and increased caspase-3 level. SUL treatment reduced mitochondrial membrane potential and induced ROS production in HepG2 cells. Finally, SUL up-regulated the gene expression levels of CuSOD and MnSOD in a dose-dependent manner but down-regulated the expression level of CAT, which may cause the accumulation of H2O2 in the HepG2 cells. These results suggested that the anti-cancer effect of SUL is mediated through the differential regulation of antioxidants, which contributes to the elevated ROS production, thereby, inducing apoptosis in the HepG2 cells.