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© 2016 The Authors. Glia Published by Wiley Periodicals, Inc. Microglia are highly plastic cells that can assume different phenotypes in response to microenvironmental signals. Lipopolysaccharide (LPS) and interferon-γ (IFN-γ) promote differentiation into classically activated M1-like microglia, which produce high levels of pro-inflammatory cytokines and nitric oxide and are thought to contribute to neurological damage in ischemic stroke and Alzheimer's disease. IL-4 in contrast induces a phenotype associated with anti-inflammatory effects and tissue repair. We here investigated whether these microglia subsets vary in their K+channel expression by differentiating neonatal mouse microglia into M(LPS) and M(IL-4) microglia and studying their K+channel expression by whole-cell patch-clamp, quantitative PCR and immunohistochemistry. We identified three major types of K+channels based on their biophysical and pharmacological fingerprints: a use-dependent, outwardly rectifying current sensitive to the KV1.3 blockers PAP-1 and ShK-186, an inwardly rectifying Ba2+-sensitive Kir2.1 current, and a Ca2+-activated, TRAM-34-sensitive KCa3.1 current. Both KV1.3 and KCa3.1 blockers inhibited pro-inflammatory cytokine production and iNOS and COX2 expression demonstrating that KV1.3 and KCa3.1 play important roles in microglia activation. Following differentiation with LPS or a combination of LPS and IFN-γ microglia exhibited high KV1.3 current densities (∼50 pA/pF at 40 mV) and virtually no KCa3.1 and Kircurrents, while microglia differentiated with IL-4 exhibited large Kir2.1 currents (∼ 10 pA/pF at −120 mV). KCa3.1 currents were generally low but moderately increased following stimulation with IFN-γ or ATP (∼10 pS/pF). This differential K+channel expression pattern suggests that KV1.3 and KCa3.1 inhibitors could be used to inhibit detrimental neuroinflammatory microglia functions. GLIA 2016;65:106–121.