Objective To observe the effect of Spred2 on apoptosis of human hepatocellular carcinoma cells. Methods HepG2 cells were transfected with pcDNA3. 0 and pcDNA3. 0-Spred2 for the morphologic change of HepG2 to be observed. Cells were stained with annexin Ⅴ conjugated to fluorescein isothiocyanate(annexin Ⅴ-FITC) and propidium iodide(PI/7-AAD) . The stained cells were analyzed on a flow cytometer using the Cellquest program. The expression level of Spred2 was examined by Western blot. Results Spred2 over-expression induced HepG2 cells apoptosis and sensitized cells to 5-FU induced HepG2 cells apoptosis. Conclusions Spred2 can regulate HepG2 cellular apoptosis.