Objective To evaluate of risperidone（ RIS） on metabolic dysfunction of female mice， and the role of macrophage migration inhibitory factor（ MIF）. Methods A total of 24 C57BL/6 female mice are randomly divided into 3 groups， and treated with vehicle， 2 mg/kg RIS， 4 mg/kg RIS for 4 weeks by intragastric administration. Then the body weight， food intake， glucose tolerance and liver weight were compared. MIF was assessed by ELISA（ Experiment 1）. To further evaluate the role of MIF in risperidone induced metabolic dysfunction， we performed experiment with MIF knockout（ MIF-/-） and wide type（ WT） mice. Mice were randomly assigned to WT+Vehicle、WT+RIS、MIF-/-+Vehicle、MIF-/-+RIS group. All groups were treated for six weeks. The body weight and food intake were compared（ Experiment 2）. Results Experiment 1： Body weight and food intake were increased most obviously after 4 mg/kg RIS treatment. A corresponding glucose resistance and elevated liver weight were observed in 4 mg/kg RIS group. Four weeks later， the body weight， food intake and the weight of liver of the 4 mg/kg RIS group were（ 19.54±0.22） g，（ 3.76±0.06） g/d，（ 0.85±0.01） g， while those of the control group were（ 18.17±0.21） g，（ 2.56±0.04） g/d，（ 0.68±0.03） g. Furthermore， the amount of MIF in 4 mg/kg RIS group was（ 33.13±1.44） ng/ml， which was higher than that of the control group （19.6±1.06） ng/ml. Experiment 2： On the 6th week of treatment， compared with MIF-/- mice， wild-type mice showed significant increase in body weigh［t （21.68±0.21） g vs（ 20.44±0.17） g］ and food intake［ （3.12±0.02） g/d vs（ 2.62±0.03） g/d］ after risperidone administration. There was no weight gain or food intake in MIF-/- + RIS group. Conclusions 4 mg/kg RIS could induce metabolic dysfunction in female C57BL/6 mice. MIF may play an important role in RIS induced metabolic dysfunction.