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Immune cells of myeloid lineage cluster around amyloid-β plaques in the Alzheimer’s disease brain. However, assigning functional roles to myeloid subtypes, namely brain-resident microglia versus peripherally derived monocytes, has been problematic. Now, Varvel et al. use a model of central nervous system myeloid cell depletion to demonstrate that repopulation by peripheral monocytes is insufficient to eliminate plaques. The findings indicate that myeloid replacement therapy by itself may not be an effective therapeutic strategy in Alzheimer’s disease., Immune cells of myeloid lineage are encountered in the Alzheimer’s disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD.