This study was aimed at analyzing the effect of disinfectants on the roughness and mechanical properties of computer-aided design/computer-aided manufacturing (CAD/CAM) polymethylmethacrylate (PMMA) dentures. Two groups of denture base resins were tested: heat-polymerized and milled blocks. The specimens were shaped (n=80) for flexural strength (FS), flexural modulus (FM), and (n=240) for the properties of roughness (Ra) and microhardness alterations (KHN). 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 the three-way analysis of variance (ANOVA). Microhardness and surface roughness were analyzed using repeatedmeasures ANOVA. A significance level of 5% was set. 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). 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. Int J Prosthodont 2023. doi: 10.11607/ijp.8301.