Objective To investigate the effect of Slit2 over-expression on nonalcoholic fatty liver disease (NAFLD) in mice. Methods Eight week male LDLR^-/- mouse and LDLR^-/-;Slit2-Tg mouse were fed a high-fat diet for 12 weeks to induce NAFLD(n=6 per group). After 12 weeks, they were taken for blood samples and dissected. The concentration of TG (triglycerides), TC(total cholesterol), LDL-C(low density lipoprotein cholesterol) and HDL-C(high density lipoprotein cholesterol)in the serum were examined respectively. Liver tissue samples were taken for HE staining to observe the morphological and pathological changes. The mRNA expression levels of hepatic genes related to lipid metabolism such as LXR-α,LXR-β FAS,SREBP-1c was measured by real-time RT-PCR. Results The serum LDL-C levels of LDLR^-/-;Slit2-Tg mouse were significantly lower than that in LDLR^-/- mouse(P < 0.01).And the grade of lipid droplets and pathological injury of liver tissue decreased significantly in the LDLR^-/-;Slit2-Tg mouse compared with LDLR^-/- mouse. Furthermore, The mRNA expression levels of hepatic genes related to lipid metabolism decreased significantly in the LDLR^-/-;Slit2-Tg mouse. Conclusions The overexpression of Slit2 can reduce the pathological injury of liver tissue in mouse with NAFLD.