Microglial reactivity is linked with the loss of dopaminergic (DA) neurons in Parkinson’s disease (PD). In this context, we propose that calcium, potentially released by DA dying neurons to the extracellular space, may contribute provoking changes in microglial polarization.Postmortem samples from PD patients exhibited increased microglia-neuron interactions in the Substantia Nigra (SN) when compared with control individuals, indicating a polarization of microglia in this pathological scenario. Besides, MPTP-treated parkinsonian mice also revealed a significant number of polarized microglia towards degenerating neurons in the SN. Then, in vitro experiments, performed with DA-specific neurotoxin MPP+, showed an increase of Ca2+ release to the extracellular space pointing to Ca2+ as a potential messenger for microglia. In vivo, intrastriatal administration of calcium in C57BL/6j mice unmasked clear differences in the polarization of microglial branches towards the source when compared to saline. Thus, calcium was proposed as the main inductor of the polarization of microglial branches.Then, we hypothesized that Iba-1 may be a crucial factor leading these polarizing changes. To ascertain the implication of Iba-1 in microglial motility, intracranial injections of calcium were also performed in Iba-1-/- mice. KO mice showed a significant impairment of Ca2+-induced branch-polarizing capacity due to the lack of Iba-1. Later studies performed in MPTP-Iba-1 KO mice revealed a slight decrease of polarized microglia compared to controls.These results suggest a novel interplay between dying DA neurons and neighboring microglial cells in which specific Ca2+-dependent responses, mediated by Iba-1, may contribute to the inflammatory reactivity in parkinsonian neurodegeneration.