Chronic treatment with antipsychotics, especially most of atypical ones, leads to development of metabolic abnormalities. Olanzapine is an atypical antipsychotic widely used in the treatment of schizophrenia and bipolar disorder. The mechanisms underlying olanzapine-induced metabolic adverse effects in the liver, however, remain unclear. This study was designed to investigate olanzapine-induced insulin-desensitivity in the liver. Male rats were treated with olanzapine (5 mg/kg, by a gavage method, once daily for consecutive 8 weeks. Blood and liver variables were determined enzymatically or histologically. Gene/protein expression was analyzed by real-time PCR and Western blot. Olanzapine treatment significantly increased fasting plasma insulin concentration, the index of the homeostasis model assessment of insulin resistance (HOMA-IR), and hepatic triglyceride and fatty droplet accumulation in rats. Hepatic gene/protein expression profile revealed that olanzapine activated mRNA and protein expression of sterol regulatory element-binding protein-1c, and mRNA levels of its downstream lipogenic enzymes, acetyl-CoA carboxylase-1, fatty acid synthase and stearoyl-CoA desaturase-1. More importantly, phosphorylated protein level of both Ser307 in insulin receptor substrate (IRS)-1 and Ser731 in IRS-2 was increased. Furthermore, phosphorylation of Tyr607 in phosphoinositide 3-kinase (PI3K) p85α, Ser473 in Akt and Ser2448 in mammalian target of rapamycin was also enhanced. Our results suggest that the IRS/PI3K/Akt signaling pathway mediates olanzapine-induced hepatic insulin resistance in male rats. Our findings may provide better understanding of the antipsychotic-induced metabolic adverse effects. Copyright © 2018. Published by Elsevier Inc.