Macrophage population in most mammalian organs consists of cells of different origin, with the exception of the central nervous system and the liver, where macrophages of monocytic origin are almost completely absent. The reasons for such distribution and the phenomenon of coexistence of the two separate macrophage lineages with different origin in mammals remain poorly understood. In present study we compared Kupffer cells and monocytes by the immunophenotype, gene expression profile, proteome and pool of mircoRNA. Observed differences do not allow to consider the resident liver macrophages as purely M2 macrophages or monocytes have purely M1 features. Two populations of macrophages of monocytic origin and resident macrophages have fundamentally different roles in maintaining homeostasis. Monocytic macrophages are involved in the regulation of inflammation, and resident macrophages are involved in the regulation of specific organ functions (nitrogen metabolism, complement system protein synthesis). However, if other indicators would be considered as markers of macrophage activity, it is worth noting that Kupffer cells possess some features of M2 macrophages. This is indicated by their expression profile of let-7b/c/d/e miRNAs, a high content of proteins associated with oxidative phosphorylation, as well as an increased level of synthesis of Arg1, IL10.