CAD/CAM (computer-aided design/computer-aided manufacturing) for indirect restorative materials has been recently introduced in dentistry. The purpose of this study was to evaluate the change of the surface micro-hardness of different restorative CAD/CAM materials after exposure to a carbonated acidic drink (Coca-Cola, Coca-Cola Company, Milan, Italy). One hundred and eighty specimens of identical size (2 mm thickness) were obtained by sectioning each tested CAD/CAM block of four materials: a hybrid ceramic (CERASMART™, GC Corporation, Tokyo, Japan), a resin nano ceramic (Lava™ Ultimate, 3M, Monrovia, CA, USA), a nanohybrid composite (Grandio blocs, VOCO GmbH, Cuxhaven, Germany), and a zirconia-reinforced lithium silicate glass ceramic (VITA SUPRINITY® PC; VITA Zahnfabrik, Bad Sackingen, Germany). Forty-five specimens of each material were tested. Micro-hardness was measured at baseline, after 7 days and after 28 days. The data were analyzed. The micro-hardness of each material varied significantly after immersion in Coca-Cola. The nanohybrid composite had a high initial micro-hardness and the greatest percentage loss after acid exposure. The hybrid ceramic and the resin nano ceramic had similar percentage losses of micro-hardness values even if the second material had higher initial values. The zirconia-reinforced lithium silicate glass ceramic had the highest baseline values and the lowest percentage loss of micro-hardness. The different CAD/CAM materials presented different micro-hardness values before and after acid exposure.