INTRODUCTION: CAD/CAM denture base materials are milled from pre-polymerized pucks of resin that are highly condensed. So, they provide no polymerization shrinkage eliminating its subsequent disadvantages. This technology offered improved fit, strength properties and more bio-hygienic denture bases compared with conventional processing of the denture base material. OBJECTIVES: The aim of the study was to evaluate the physico-mechanical properties of CAD/CAM denture base material and the effect of thermo-cycling on it compared with the conventional one. MATERIALS AND METHODS: The study was conducted on two parallel groups, divided according to the denture material used. Group (1) conventional PMMA (control group), group (II) CAD/CAM PMMA (study group) of 40 specimens each (16 for impact strength, 16 for flexural strength, 8 for surface roughness and grinded powder form both materials for residual monomer test). Each group was divided into 2 subgroups: (A) No thermo-cycling and (B) Thermo-cycling, then subjected to 4 different tests, impact strength, flexural strength, surface roughness and residual monomer tests. Data were collected, tabulated and statistically analyzed. Significance level was set at 5%. Bar charts were used for graphical presentations. RESULTS: Our study revealed a highly statistically significant decrease in residual monomer of CAD/CAM PMMA material in both conditions before and after thermo-cycling when compared to conventional PMMA material, which therefore leads to enhanced impact strength and significantly reduced surface roughness after heat treatment. On the other hand, also a highly significant reduction of its flexural strength after thermocycling has been observed. CONCLUSIONS: CAD/CAM dentures with lower amount of methacrylate monomer exhibit more favourable physico-mechanical properties and they have a long-term biocompatibility even with thermal changes making them a more satisfactory as a denture base material for edentulous patients.