Purpose: The purpose of this in vitro study was to evaluate and compare the surface roughness (Ra) and adhesion of Candida albicans (C. albicans) on conventional heat-cured, injection-molded thermoplastic resin and computer-aided design/computer-aided manufacturing (CAD-CAM) denture base resin as affected by denture cleanser solution at baseline, 15, 30, and 45 days. Materials and methods: A rectangular-shaped metal die was fabricated to make heat-cure (n = 80) and injection-molded thermoplastic denture base resin (n = 80) disks of uniform dimensions, whereas CAD-CAM disks (n = 80) were made by scanning the wax disk and milling of polymethylmethacrylate (PMMA) block. All the 240 specimens were immersed in the two different solutions, that is, artificial saliva solution (n = 120) as the control group and denture cleansing solution (n = 120) as a test group for a period of 0, 15, 30, and 45 days for 8 hours, respectively followed by Candida colonization. The Ra was evaluated by surface profilometer SJ-201, followed by the measurement of Candida colonization. The statistical analysis was done using repeated measures analysis of variance (ANOVA) test, one-way ANOVA, and independent t-test. Results: The Ra of heat-cured cured samples were 0.87 ± 0.01, 0.85 ± 0.02, 0.84 ± 0.02, and 0.83 ± 0.02 μm; injection-molded thermoplastic resin samples were 1.03 ± 0.01, 1.03 ± 0.04, 1.02 ± 0.03, and 1.00 ± 0.05 μm; and of CAD-CAM resin samples were 0.42 ± 0.01, 0.41 ± 0.02, 0.40 ± 0.03, and 0.40 ± 0.03 μm, respectively, when immersed in artificial saliva at baseline and intervals of 15, 30, and 45 days. The Ra of heat-cured samples were 1.12 ± 0.011, 1.21 ± 0.008, 1.25 ± 0.011, and 1.56 ± 0.008 μm; injection-molded thermoplastic resin samples were 1.31 ± 0.010, 1.45 ± 0.008, 1.76 ± 0.010, and 2.26 ± 0.014 μm; and of CAD-CAM resin samples were 0.86 ± 0.016, 1.07 ± 0.008, 1.12 ± 0.008, and 1.18 ± 0.015 μm, respectively, when immersed in denture cleansing solution at baseline, 15, 30, and 45 days. A similar trend was visible in the adherence of Candida to the denture base resins; the least adherence was seen in CAD-CAM resin, followed by heat-cured resin and injection-molded thermoplastic denture base resins. Conclusion: Within the limitations of the study, it was concluded that CAD-CAM denture base resins may be the preferred choice over conventional heat-cured or thermoplastic denture base resins for the fabrication of removable dental prosthesis to minimize Candida adherence and thus preventing opportunistic fungal infections in geriatric individuals.