Inflammation is a key pathological process in the progression of atherosclerosis and type 2 diabetes. 12/15-lipoxygenase (12-LO), an enzyme involved in fatty acid metabolism, may contribute to inflammatory-mediated damage triggered by stressors such as obesity and insulin resistance. We hypothesized that mice lacking 12-LO are protected against inflammatory-mediated damage associated with a high fat 'western' diet (HFD). To test this hypothesis, age-matched male 12-LO knockout (12-LOKO) and wild type C57Bl/6 (B6) mice were fed either a standard chow or HFD and assessed for several inflammatory markers. HFD B6 mice showed expected reductions in glucose and insulin tolerance compared to chow-fed mice. In contrast, HFD-fed 12-LOKO mice maintained similar glucose and insulin tolerance to chow-fed mice. Circulating proinflammatory adipokines, TNF-alpha and IL-6, were increased in HFD B6 mice but not 12-LOKO mice, whereas the reported protective adipokine, adiponectin, was decreased only in HFD B6 mice. 12-LO activity was significantly elevated by HFD in pancreas and fat from B6 mice. In visceral fat, macrophage numbers and MCP-1 expression were elevated in HFD B6 mice, but not 12-LOKO. Islets from 12-LOKO mice did not show HFD-induced islet hyperplasia nor increases in caspase-3 apoptotic staining observed in HFD B6 mice. Islets from 12-LOKO mice were also protected from reduced glucose-stimulated insulin secretion observed in islets from HFD-fed B6 mice. These data suggest 12-LO activation may play a role in HFD-induced toxicity in visceral fat and islets. Inhibiting 12-LO may provide a new therapeutic approach to prevent inflammatory-mediated metabolic consequences of excess fat intake.