Carbon monoxide participates in many copper-catalyzed reactions, which makes CO-induced structural changes of Cu catalysts key for important industrial processes. We have studied the interaction of carbon monoxide with the Cu(100) single crystal termination at 120, 200, and 300 K by means of low-energy electron diffraction (LEED), temperature-programmed desorption (TPD), X-ray photoelectron spectroscopy (XPS), polarization-modulation infrared reflection absorption spectroscopy (PM-IRAS), and density functional theory (DFT) calculations. The absorption band of CO (2082–2112 cm–1) at elevated gas pressure (up to 5 mbar) and at 200/300 K was found at a higher wavenumber than the characteristic band of the c(2 × 2)CO structure and was consistent with CO adsorbed on low-coordinated Cu atoms. The combined PM-IRAS/DFT analysis revealed that exposure to CO induced surface roughening through the formation of Cu adatoms and clusters on the (100) terraces. The roughened surface seemed surprisingly active for CO dissociation, which indicates its unique catalytic properties.