Purpose: The purpose of this study was to explore the clinical importance of the effect of Prevident and chlorhexidine on the surface roughness of three commonly utilized lithium disilicate ceramics: pressed (Press), milled (CAD), milled and veneered with fluorapatite (CAD/CERAM). Methods and Materials: Seventy-six rectangular specimens in each group of Press, CAD, and CAD/CERAM were fabricated. A profilometer was used to measure the surface roughness prior to and after soaking. The samples were immersed in the assigned anti-caries solution in an airtight plastic container. For the simulation of 2 years use the samples were soaked in chlorhexidine for 3 hours, Prevident, 6% alcohol and distilled water for 12 hours. Statistical analysis was completed using a two-way ANOVA followed by Tukey's HSD test. A p value ≤.05 was considered significant. Results: The results demonstrated that Press samples became significantly rougher. In addition to that, the surface roughness of CAD and CAD/CERAM was significantly decreased. However, CAD was significantly less rough than CAD/CERAM. Water did not significantly change the surface roughness of ceramics, while 6% alcohol, Prevident, and chlorhexidine significantly decreased the roughness of the ceramics. There was no significant difference in the increase of surface smoothness among the three solutions. A significant interaction was found only with water, the control. Conclusion: Within the limitations of this study, it can be concluded that Prevident and chlorhexidine can change the surface roughness of lithium disilicate ceramics when used for a period of 2 years. The surface roughness of Press increased, while that of CAD and CAD/CERAM decreased.