Tauopathies are a broad set of neurodegenerative dementias characterized by the aggregation of Tau protein. Activated microglia and elevated levels of pro-inflammatory molecules are also pathological hallmarks of tauopathies. In these diseases, intracellular Tau is secreted to the extracellular space, where it interacts with other cells, such as neurons and glia, promoting inflammation. However, the mechanism through which extracellular Tau triggers pro-inflammatory responses in microglia remains unknown. Primary microglia cultures were treated with extracellular Tau in its hyperphosphorylated, dephosphorylated or non-phosphorylated form. Protein cytokine arrays, real-time PCR, inhibition of the p38 MAPK pathway, phosphatase assays, and quantification of proteins through immunoblotting were used to analyze the effect of extracellular Tau on the pro-inflammatory response of microglia. The main finding of this work is that extracellular non-phosphorylated and dephosphorylated forms of Tau, rather than hyperphosphorylated Tau, activate the p38 MAPK pathway in microglia, thus triggering a pro-inflammatory response in these cells.