Purpose: The objectives of this in vitro study were to evaluate the flexural strength (FS), surface roughness (Ra), and hydrophobicity of polymethylmethacrylate (PMMA)-based computer-aided design/computer-aided manufacturing (CAD/CAM) polymers and to compare the properties of different CAD/CAM PMMA-based polymers with conventional heat-polymerized PMMA following thermal cycling. Materials and methods: Twenty rectangular-shaped specimens (64 × 10 × 3.3 mm) were fabricated from three CAD/CAM PMMA-based polymers (M-PM Disc [M], AvaDent Puck Disc [A], and Pink CAD/CAM Disc Polident [P], and one conventional heat-polymerized PMMA (Promolux [C]), according to ISO 20795-1:2013 standards. The specimens were divided into two subgroups (n = 10), a control and a thermocycled group. The specimens in the thermocycled group were subjected to 5000 thermal cycling procedures (5 to 55°C; 30 s dwell times). The Ra value was measured using a profilometer. Contact angle (CA) was assessed using the sessile drop method to evaluate surface hydrophobicity. In addition, the FS of the specimens was tested in a universal testing machine at a crosshead speed of 1.0 mm/min. Surface texture of the materials was assessed using scanning electron microscope (SEM). The data were analyzed using two-way analysis of variance (ANOVA), followed by Tukey's HSD post-hoc test (α 0.05). Results: CAD/CAM PMMA-based polymers showed significantly higher FS than conventional heat-polymerized PMMA for each group (P 0.001). CAD/CAM PMMA-based polymer [P] showed the highest FS, whereas conventional PMMA [C] showed the lowest FS before and after thermal cycling (P 0.001). There were no significant differences among the Ra values of the tested denture base polymers in the control group (P > 0.05). In the thermocycled group, the lowest Ra value was observed for CAD/CAM PMMA-based polymer [M] (P 0.001), whereas CAD/CAM PMMA-based polymers [A] and [P], and conventional PMMA [C] had similar Ra values (P > 0.05). Conventional PMMA [C] had a significantly lower CA and consequently lower hydrophobicity compared to the CAD/CAM polymers in the control group (P 0.001). In the thermocycled group, CAD/CAM PMMA-based polymer [A] and conventional PMMA [C] had significantly higher CA, and consequently higher hydrophobicity when compared to CAD/CAM polymers [M] and [P] (P 0.001). However, no significant differences were found among the other materials (P > 0.05). Conclusions: The FS and hydrophobicity of the CAD/CAM PMMA-based polymers were higher than the conventional heat-polymerized PMMA, whereas the CAD/CAM PMMA-based polymers had similar Ra values to the conventional PMMA. Thermocycling had a significant effect on FS and hydrophobicity except for the Ra of denture base materials. Keywords: CAD/CAM, digital complete dentures, flexural strength (FS), hydrophobicity, PMMA, surface roughness (Ra)