Obesity is linked to increased risk of Alzheimer's disease and cognitive impairment. Microglia-mediated neuroinflammation is implicated in neuronal loss. Elevated levels of fatty acids seen in obesity induce inflammation in peripheral tissues. Whether fatty acids promote neuroinflammation is unknown. Using an established neuroinflammation model involving human microglia-like THP-1 cells and SH-SY5Y neuroblastoma cells, we show that the saturated fatty acid palmitate, but not the unsaturated fatty acids oleate or linoleate, induces THP-1 cell pro-inflammatory cytokine secretion and neurotoxicity. Inhibition of c-Jun NH2-terminal kinase (JNK) reduces this neurotoxicity. Therefore, elevated saturated fatty acids may induce neuroinflammation through pathways involving JNK activation.