Overexpression of lipoprotein lipase (LPL) protects against atherosclerosis in genetically engineered mice. We tested whether a gene therapy vector that delivers human (h) LPL S447X cDNA to skeletal muscle could induce similar effects.LDL receptor knockout (LDLr−/−) mice were injected intramuscular (IM) with adeno-associated virus serotype 1 (AAV1) LPL S447X or PBS. Four weeks later they were started on an atherogenic diet for 12 weeks. After termination, atherosclerosis was assessed and homogenates of muscle and liver tissue were analyzed.AAV1-treated mice showed hLPL concentrations of 768±293ng/mL in post-heparin plasma associated with 48% reductions of fasting triglycerides (TG) levels (p<0.0001). In the absence of an effect on total cholesterol (TC) levels, no effects on atherosclerosis were found. An increase in lipid content of injected muscles was accompanied by a significant decrease of TG (−20%, p<0.0001) and free cholesterol (FC) content (−24%, p<0.0001) in liver homogenates.The data show that transgenic hLPL S447X on top of endogenous murine LPL reduces fasting TG levels in plasma but has no effect on atherosclerosis in LDLr−/− mice. While lipid accumulation in the injected muscle was anticipated, this coincided with an interesting decrease of both TG and FC in liver homogenates.