The central nervous system (CNS) homeostasis is principally maintained by brain-resident macrophages that are divided into parenchymal microglia and non-parenchymal border-associated macrophages (BAMs). During inflammation or injury, local tissue debris or pro-inflammatory mediators can attract monocyte-derived macrophages (MDMs) to migrate into the tissue. During aging, there is an increase in the proportion of MDMs in the CNS, and accumulating evidence supports their pathogenic role in neurodegenerative disease. However, the precise role of MDMs, whether they are protective or detrimental is context dependent, but remains elusive in aging. To investigate the role of MDMs infiltration in the CNS and discern age-related changes, we used the CX3CR1cre-Rosa26DTA mouse model to induce a tamoxifen dependent microglia depletion in young (2 months) and old mice (24 months) mice. The mice received 3 doses of intraperitoneal tamoxifen injection to deplete microglia. To maximize the infiltration of MDMs in the brain, the mice received two rounds of additional tamoxifen-induced depletion within the time window of 3 weeks. Seven days post last tamoxifen injection, mice were sacrificed and myeloid and lymphoid cells isolated from brains were analyzed with flow cytometry. In young mice microglial repopulation was observed after tamoxifen-induced microglial ablation. However, the capacity of microglia to repopulate in old mice was abolished. Infiltration of MDMs occurred in the brains of young and old mice, with further enrichment in aged mice. Concomitantly, increased inflammatory T-cells infiltration was observed in the brains in aging in the absence of microglia repopulation. Our findings suggest that MDMs infiltration into the CNS may cause a detrimental effect, triggering a pro-inflammatory response, especially in aging.