Microglia move toward inflammatory sites in the brain and mediate defensive responses, but cellular consequences underlying these are yet obscure. One proposed process is that nucleotide leakage or release from injured cells is sensed by metabotropic and ionotropic purinergic receptors, which may trigger long-term intracellular Ca2+ flux and cytokine release. We have successfully visualized long-term intracellular Ca2+ mobilizations related to these events using a MG5 microglial cell line expressing yellow cameleon (Ikeda et al, BBA Mol Cell Res 2013). We have also demonstrated increased expression of scavenging receptor, MARCO, in MG5 cells or in primary cultures of mouse microglia following ATP stimulations. Thus, the present study further analyzed function of MARCO for the Ca2+ mobilizations and cell migrations in MG5 cells. First, the effect of fucoidan (a general scavenger receptor antagonist) was examined by continuous (9-h) video-monitoring of cell migrations. The results demonstrated significant suppression of cell migrations in a concentration-dependent manner (1-500 μg/ml) having little effects on cell survivability. In addition, siRNA targeted to MARCO was co-transfected with yellow cameleon into MG5 cells to monitor the effects on Ca2+ mobilizations and cell migrations. Interestingly, we observed reduction of cellular ruffling and decrease in the size of purinergic responses by the MARCO siRNA. These results suggest critical function of MARCO for microglial immune responses.