To overcome the efficiency-cytotoxicity dilemma of native PEI and incorporate the advantages of alginate, we designed a novel gene vector by grafting PEI 2000 onto alginate, an anionic polysaccharide with excellent biocompatibility. The alginate-graft-PEI (Alg-g-PEI) was successfully synthesized and then characterized by elemental analysis, (1)H-NMR and (13)C-NMR. The M(w) of Alg-g-PEI is ca. 17 000. Acid-base titration confirmed that Alg-g-PEI retained the buffering capacity of native PEI. The DNA binding ability of the polymer was confirmed by gel retardation assay. DSL analysis showed that Alg-g-PEI had a particle size and zeta-potential similar to PEI 25K. AFM detected a clear and well-shaped morphology of the complexes. Additionally, Alg-g-PEI exhibited lower cytotoxicity than PEI 25K in BEL7402, MSC and RVMSC cells. Compared with PEI 25K, Alg-g-PEI had comparable or even higher transfection efficiency. Similarly, Alg-g-PEI-mediated VEGF expression was significantly higher compared with PEI 25K-mediated VEGF expression. All together, our results suggest that Alg-g-PEI has a potential to be a safe and efficient agent for gene therapy.