Olanzapine is a second-generation anti-psychotic drug used to prevent neuroinflammation in patients with schizophrenia. However, the long-term administration of olanzapine leads to insulin resistance (IR); the mechanisms of this effect remains poorly understood. Using cellular and rodent models of IR induced by olanzapine, we found that chronic olanzapine treatment induces differential inflammatory cytokine reactions in peripheral adipose and the central nervous system. Long-term treatment of olanzapine caused metabolic symptoms, including IR, by markedly elevating the plasma levels of pro-inflammatory cytokines, including IL-1ß, IL-6, IL-8 and TNFα; these findings are consistent with observations from schizophrenia patients chronically treated with olanzapine. Our observations of differential inflammatory cytokine responses in white adipose tissues from the prefrontal cortex in the brain indicated cell type-specific effects of the drug. These cytokines induced IR by activating NF-kB through the suppression of IkBα. Functional blockade of the components p50/p65 of NF-kB rescued olanzapine-induced IR in NIH-3T3 L1-derived adipocytes. Our findings demonstrate that olanzapine induces inflammatory cytokine reactions in peripheral tissues without adversely affecting the central nervous system and suggest that chronic olanzapine treatment of schizophrenia patients may cause inflammation-mediated IR with minimal or no adverse effects in the brain.