Purpose: To analyze the effect of disinfectants on the roughness and mechanical properties of CAD/ CAM polymethylmethacrylate (PMMA) dentures. Materials and Methods: Two groups of denture base resins were tested—heat-polymerized and milled blocks. For each resin, 120 specimens were produced for flexural strength (FS) and flexural modulus (FM) analyses (total: 240 specimens), and 40 were produced for microhardness and surface roughness evaluations (total: 80 specimens). They were categorized into the following groups based on immersion: control (deionized water); H1 (1% sodium hypochlorite); H05 (0.5% sodium hypochlorite); and C2 (2% chlorhexidine) groups. The immersion periods were 0 (T0), 130 (T1), and 260 (T2) cycles. Statistical analyses were performed for flexural properties using threeway ANOVA. Microhardness (KHN) and surface roughness (Ra) were analyzed using repeated-measures ANOVA. A significance level of 5% was set. Results: CAD/CAM PMMA showed higher FS (P = .001) and FM (P < .001) than conventional PMMA. The KHN value was superior to the conventional PMMA (P < .001). The chemical solution affected the surface roughness of both resins (P = .007). The CAD/ CAM PMMA block showed increased Ra values when H1 was used. Cycling separately increased the FS of conventional PMMA (T1 vs baseline; P < .05). However, the FM of CAD/CAM PMMA was higher (T1 and T2 vs baseline; P < .05). The time factor increased the microhardness of both resins (T2 vs baseline; P < .05). Conclusions: The CAD/CAM resin showed higher values compared to conventional PMMA in all tests, regardless of the chemical solution used; however, the values obtained for both resins were clinically acceptable.