To investigate the effect of acidic media, including beverages and gastric fluids on flexural strength and fatigue of CAD-CAM materials. Four CAD-CAM materials (high-translucency zirconia (Ceramill Zolid HT+), lithium disilicate (IPS e-max CAD), hybrid ceramic (Vita Enamic), and nanohybrid resin composite (Grandio Blocs) were prepared and immersed in one of five media (gastric HCl, white wine, Coca-Cola, orange juice, and artificial saliva) in an incubator (37℃, 24h). Surface topography and roughness were obtained using a scanning electron microscope (SEM) and a stylus contact profilometer, respectively. Initial 3-point flexural strength was measured for half of the bars (n=20/gp) using a universal testing machine (0.5mm/min). The other bars underwent 106 cyclic fatigue loadings before measurement of residual 3-point flexural strength. Data were statistically analyzed (two-way and three-way ANOVA, Tukey's post-hoc, p<0.05). Weibull distributions were plotted for reliability analysis. Zirconia bars has the highest initial flexural strengths followed by lithium disilicate, while resin composite and hybrid ceramic groups had the lowest strength regardless of the erosive medium. Cyclic fatigue significantly reduced initial flexural strengths for all materials except for hybrid ceramic and resin composite. Weibull moduli were the highest for zirconia, lithium disilicate and resin composite and lowest for hybrid ceramic. Erosive media significantly changed surface roughness of CAD-CAM materials except for zirconia and resin composite without jeopardizing the flexural strength of the CAD-CAM materials. Despite the higher flexural strengths for zirconia and lithium disilicate, resin composite and hybrid ceramic were more resistant to cyclic fatigue.