Abstract: Objective To establish liver-speci fic leukemia-related protein 16 (LRP16) gene knockout mice model, and investigate the relationship between LRP16 gene and insulin resistance. Methods The knockout vector targeting exon 5 to exon 8 of LRP16 gene was constructed by molecular cloning and transfected to embryonic stem (ES) cell by electroporation.The selected positive ES cells was microinjected into the blastula of C57BL/6J mice.And the chimerical mice were born after transplantation of blastula into host mice.The LRP16-Loxp mice were born by crossing between chimerical mice and C57BL/6J mice, and the liver-speci fic LRP16 knockout mice were obtained by crossing between LRP16-Loxp mice and Alb-Cre mice. Results Eight positive ES cell cloning strains were obtained, and 2 chimerical mice, 1 LRP16-Loxp mouse and 2 liver-speci fic LRP16 knockout mice were obtained to meet the research demand. Conclusion Liver-speci fic LRP16 knockout mice model is successfully established, which will be helpful in studying the correlation between LRP16 and insulin resistance.