Objective To establish a combined hypercholesterolemic/hypertriglyceridemic mouse model by cross-breeding of LPL and ApoE knockout mice. Methods The model was developed by crossbred, backcross and intercross of the 2 lines of knockout mice, and rescued by muscular expression of a LPL beneficial mutant in homozygous neonates. The genotype was determined by PCR and confirmed by blood lipid assay. Results The LPL and ApoE double knockout mice could be rescued by muscular expression of LPL. Plasma TG and TC levels in adult LPLO/ApoEO mice were increased 76 and 14 fold, respectively, compared with wild-type littermates. Conclusion hypercholesterolemic/hypertriglyceridemic mouse model has been developed successfully.