Benzene is a ubiquitous pollutant associated with hematotoxicity but its metabolic effects are unknown. We sought to determine if and how exposure to volatile benzene impacted glucose handling. We exposed wild type C57BL/6 mice to volatile benzene (50ppm x 6h/d) or HEPA-filtered air for 2 or 6wk and measured indices of oxidative stress, inflammation and insulin signaling. Compared to air controls, we found that mice inhaling benzene demonstrated increased plasma glucose (p = 0.05), insulin (p = 0.03), and HOMA-IR (p = 0.05), establishing a state of insulin and glucose intolerance. Moreover, insulin-stimulated Akt phosphorylation was diminished in the liver (p = 0.001) and skeletal muscle (p = 0.001) of benzene-exposed mice, accompanied by increases in oxidative stress and NF-κB phosphorylation (p = 0.025). Benzene-exposed mice also demonstrated elevated levels of MIP1-α transcripts and SOCS1 (p = 0.001), but lower levels of IRS-2 tyrosine phosphorylation (p = 0.0001). Treatment with the superoxide dismutase mimetic, TEMPOL, reversed benzene-induced effects on oxidative stress, NF-κB phosphorylation, SOCS1 expression, IRS-2 tyrosine phosphorylation, and systemic glucose intolerance. These findings suggest that exposure to benzene induces insulin resistance and that this may be a sensitive indicator of inhaled benzene toxicity. Persistent ambient benzene exposure may be a heretofore unrecognized contributor to the global human epidemics of diabetes and cardiovascular disease. Tox Sci, 2018 (in press)