Mice have a strong ability to eliminate renal calcium oxalate crystals, and our previous examination indicated a susceptibility in which monocyte‐macrophage interaction could participate in the phenomenon. To clarify the macrophage‐related factors playing roles in the prevention of crystal formation in mouse kidneys, morphologic and expression studies based on microarray pathway analysis were performed. Eight‐week‐old male C57BL/6N mice were administered 80 mg/kg of glyoxylate by daily intraabdominal injection for 15 days, and the kidneys were extracted every 3 days for DNA microarray analysis. Based on the raw data of microarray analysis, pathway analyses of inflammatory response demonstrated macrophage activation through the increased expression of chemokine (C‐X‐C) ligand 1, fibronectin 1, and major histocompatability (MHC) class II. Association analysis of related gene expression values by quantitative reverse transcription polymerase chain reaction (RT‐PCR) indicated the high association of chemokine (C‐C) ligand 2, CD44, colony‐stimulating factor 1, fibronectin 1, matrix gla protein, secreted phosphoprotein 1, and transforming growth factor β1 (TGF‐β1) with the amount of both renal crystals and F4/80, a macrophage marker. Immunohistochemically, interstitial macrophages increased during the experimental course, and CD44 and MHC class II were upregulated around crystal‐formation sites. Ultrastructural observation of renal macrophages by transmission electron microscopy indicated interstitial macrophage migration with the phagocytosis of crystals. In conclusion, increased expression of inflammation‐related genes of renal tubular cells induced by crystal formation and deposition could induce monocyte‐macrophage migration and phagocytosis via the interaction of CD44 with osteopontin and fibronectin. Such crystal‐removing ability of macrophages through phagocytosis and digestion might become a new target for the prevention of stone formation. © 2010 American Society for Bone and Mineral Research.