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Purpose Phosphorus is an essential nutrient involved in many pathobiological processes. Less than 1\% of phosphorus is found in extracellular fluids as inorganic phosphate ion (Pi) in solution. High serum Pi level promotes ectopic calcification in many tissues, including blood vessels. Here, we studied the effect of elevated Pi concentration on macrophage polarization and calcification. Macrophages, present in virtually all tissues, play key roles in health and disease and display remarkable plasticity, being able to change their physiology in response to environmental cues. Methods and results High-throughput transcriptomic analysis and functional studies demonstrated that Pi induces unpolarized macrophages to adopt a phenotype closely resembling that of alternatively -activated M2 macrophages, as revealed by arginine hydrolysis and energetic and antioxidant profiles. Pi-induced macrophages showed an anti-calcifying action mediated by increased availability of extracellular ATP and pyrophosphate. Conclusion We conclude that the ability of Pi-activated macrophages to prevent calcium-phosphate deposition is a compensatory mechanism protecting tissues from hyperphosphatemiainduced pathologic calcification. The Spanish Ministerio de Economia y Competitividad (MINECO) supports R.V.-B. (Juan de la Cierva JCI-2011-09663 and SAF-201460699-JIN postdoctoral contracts) and M.R.H. (FPI predoctoral contract BES-2011-043938). This study was supported by research grants to V.A. from MINECO (SAF2013-4663-R) and the Institute de Salud Carlos III (RD12/0042/0028) with co-funding from the Fondo Europeo de Desarrollo Regional (FEDER). The CNIC is supported by the MINECO and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí