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p27(kip1) is a multifunctional protein that promotes cell cycle exit by blocking the activity of cyclin/cyclin-dependent kinase complexes as well as migration and motility via signaling pathways that converge on the actin and microtubule cytoskeleton. Despite the broad characterization of p27(kip1) function in neural cells, little is known about its relevance in microglia. Here, we studied the role of p27(kip1) in microglia using a combination of in vitro and in situ approaches. While the loss of p27(kip1) did not affect microglial density in the cerebral cortex, it altered their morphological complexity in situ. However, despite the presence of p27(kip1) in microglial processes, as shown by immunofluorescence in cultured cells, loss of p27(kip1) did not change microglial process motility and extension after applying laser-induced brain damage in cortical brain slices. Primary microglia lacking p27(kip1) showed increased phagocytic uptake of synaptosomes, while a cell cycle dead variant negatively affected phagocytosis. These findings indicate that p27(kip1) plays specific roles in microglia. J.B. is a Ph.D. student supported by the Special Research Foundation from Hasselt University and Université de Liège. Y.A.A is supported by an FWO senior postdoctoral fellowship (12H8220N), and S.K. is a Ph.D. assistant supported by Hasselt University, J.-M.R. is a full Professor at Hasselt University, B.B. is an Associate Professor at Hasselt University and L.N. is Director from the F.R.S.-F.N.R.S. This work was supported by the Special Research Foundation (BOF17DOCLI01), the FWO research grant (1521619N), Funding Hercules (I000220N), the Sint-Gillis autism research grant, ROTARY Espoir en Tête—Hoofdzaak er is Hoop, the F.R.S.-F.N.R.S. (Synet; EOS 0019118F-RG36), the Fonds Leon Fredericq (L.N.), the Fondation Médicale Reine Elisabeth (L.N.), the Fondation Simone et Pierre Clerdent (L.N), the Belgian Science Policy (IAP-VII network P7/20 (L.N.)), and the ERANET Neuron STEM-MCD and NeuroTalk (L.N.). We sincerely thank Melissa Jans and Yennick Geuens for the maintenance of the mouse colonies at BIOMED and Petra Bex and Fanny Lepiemme for providing assistance in maintaining the mouse colonies at BIOMED or the GIGA research institute. We thank Rosette Beenaerts for technical assistance with RT-PCR and Sam Duwé from the BIOMED Imaging platform for his technical support. We also thank Sandra Ormenese, Jean-Jaques Goval (deceased), and Rafaat Stephan from the GIGA-Cell imaging and flow cytometry platforms for their technical guidance