The study evaluated the effect of different acidic salivary pH values on monomer leaching and surface roughness of conventional and CAD/CAM processed (milled and 3D-printed) denture base materials. High-performance liquid chromatography was used to determine the quantity of residual methyl methacrylate monomer leaching after 30 days of immersion in acidic saliva. The surface roughness (Ra) before and after incubation was recorded using a non-contact optical profilometer. The monomer leaching and the surface roughness of the tested materials depended on the pH value of the saliva. The conventional denture framework material exhibited the highest and lowest leaching rates at pH=4.5 and pH=3.5, respectively, regardless of the treatment method. Among the CAD/CAM processed materials, the 3D-printed material showed the highest and lowest leaching at pH=5.5 and pH=3.5, respectively. Regardless of the pH, roughness after incubation was the lowest for conventional materials, and the highest for 3D printing.