AIMS: The present study aimed to investigate the possible effects of metformin on the olanzapine-induced insulin resistance in rats. METHODS: Rats were randomly divided into three groups: the control (Control) group, the olanzapine (Ola) group and the olanzapine + metformin (Ola + Met) group. Rats in the Ola group received olanzapine (8 mg/kg/day) intraperitoneally while rats in the Ola + Met group received olanzapine (8 mg/kg/day) intraperitoneally and metformin (300 mg/kg/day) orally for 8 weeks. Rats in the Control group received vehicle accordingly. Body weight and fasting blood glucose were recorded routinely. Inflammatory cytokines TNF-α, IL-6 and IL-1β and IL-10 were measured by ELISA. The gene expression of macrophages markers was examined by qPCR. The epididymal white adipose tissue, liver and skeletal muscle were also isolated for immunohistochemical analysis. RESULTS: Olanzapine significantly induced body weight gain and insulin resistance compared to the control, which was markedly alleviated by metformin. Pro-inflammatory cytokines TNF-α, IL-6 and IL-1β were upregulated while the anti-inflammatory cytokine IL-10 was downregulated by olanzapine in plasma and epididymal white adipose tissue compared to the control, but not the liver and skeletal muscle. However, metformin co-administration significantly decreased the levels of TNF-α, IL-6 and IL-1β while increased the level of IL-10 in epididymal white adipose tissue compared to olanzapine-treated rats. Moreover, olanzapine treatment markedly increased the expression of the CD68 and the M1 macrophage markers while decreased the expression of the M2 macrophage markers in epididymal white adipose tissue in rats compared to the control. However, metformin co-treatment ameliorated the effects of olanzapine. CONCLUSIONS: Our results suggest that metformin alleviated olanzapine-induced insulin resistance possibly by suppressing the inflammatory responses mediated by macrophage infiltration and polarization in epididymal white adipose tissue.