Background: Microglia are the resident immune cells in the brain, which show a broad spectrum of phenotypes ranging from the pro-inflammatory, potentially cytotoxic to the anti-inflammatory, scavenging, and regenerative. Fatty-acid binding protein 5, an intracellular protein that are important for cellular metabolism, have been identified in human and mouse microglia; however, its role in microglia is yet to be defined. Studies from our laboratory and others have shown that FABP5 is downregulated in the brain of Alzheimer’s disease patients and APP/PS1 mice. This study is to explore the impact of FABP5-deficiency on microglia phenotype. Method: Total protein from FABP5-knockout mouse brains (4-5 months old) was extracted to assess cytokine levels (TNFα, IL-1ß). Microglia abundance in the hippocampus of FABP5-knockout mice and their wildtype control mice was quantified immunohistochemically. FABP5 in the immortalized mouse microglia BV2 was downregulated using siRNA, and the metabolism of the treated microglia was assessed via [3H]-2-deoxy-D-glucose (2dg) uptake and oleic acid oxidation assay. Result: A significant increased levels of TNFα (1.4-fold) and IL-1ß (1.25-fold) was detected in the brain homogenates of FABP5-knockout mice (vs wildtype control mice). Interestingly, a higher abundance (8%) of microglia was observed in the hippocampus of the FABP5-knockout mice. The downregulated FABP5 in BV2 using siRNA and achieved a 76.4% reduction in FABP5 protein expression. We subsequently observed a 1.5-fold elevation of 3H-2dg uptake in FABP5-downregulated BV2 cells, suggesting a possible increase in glycolysis. This shift was in agreement with the metabolism requirement of the proinflammatory microglia. Conclusion: Further studies need to be performed to confirm the role of FABP5 in microglia. Our data supports that FABP5 deficiency possibly leads to microglia proinflammatory activation and contribute to neuroinflammation in mice.