Purpose: To investigate the in vitro effect of four different mouthrinses on discoloration of popular CAD-CAM blocks. Methods: 40 specimens were prepared and then were divided into five groups (n = 8) for each CAD-CAM block (Vitablocks Mark II, IPS e-max CAD, GC LRF, Enamic, Cerasmart). In total, four different mouthrinses for each group (Listerine Zero, Parodontax, Kloroben, Oral B Pro-Expert) and distilled water for the control group were used. The specimens were immersed in 20 ml solution for 2 minutes, twice a day for 21 days with a 12-hour interval. Color changes were measured with a digital spectrophotometer (Vita Easyshade) after 7, 14 and 21 days and specimens were prepared. For statistical analysis, color changes (Delta E) were calculated and Kruskal Wallis and Wilcoxon tests were used. Results: There was not a significant difference in Delta E1 and Delta E2 values (P> 0.005) while there was a significant one in Delta E3 (P= 0.001) after Bonferroni correction for CAD-CAM materials were carried out as it is independent of the mouthrinse. Listerine Zero brought about the most noticeable color change in all CAD-CAM materials except e.Max after 21 days.