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A central neuropathological finding in the <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mouse, an animal model for EPM1, is early microglial activation, which precedes astroglial activation, neuronal loss, and onset of myoclonus, thus implying a critical role for microglia in EPM1 pathogenesis. Here, we characterized phenotypic and functional properties of microglia from <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice utilizing brain tissue, microglia directly isolated from the brain, and primary microglial cultures. Our results show significantly higher <jats:italic>Cstb<\/jats:italic> mRNA expression in microglia than in neurons and astrocytes. In <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mouse brain, expression of the inflammatory marker p\u2010p38 MAPK and the proportion of both pro\u2010inflammatory M1 and anti\u2010inflammatory M2 microglia is higher than in control mice. Moreover, M1\/M2 polarization of microglia in presymptomatic <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mice is, compared to control mice, skewed towards M2 type at postnatal day 14 (P14), but towards M1 type at P30, a time point associated with onset of myoclonus. At this age, the high expression of both pro\u2010inflammatory inducible nitric oxide synthase (iNOS) and anti\u2010inflammatory arginase 1 (ARG1) in <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> mouse cortex is accompanied by the presence of peripheral immune cells. Consistently, activated <jats:italic>Cstb<jats:sup>\u2212\/\u2212<\/jats:sup><\/jats:italic> microglia show elevated chemokine release and chemotaxis. However, their MHCII surface expression is suppressed. Taken together, our results link CSTB deficiency to neuroinflammation with early activation and dysfunction of microglia and will open new avenues for therapeutic interventions for EPM1. 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