Aim:To compare between conventional heat cured Acrylic resin and Flexible thermoplastic resin denture base materials on microbial colonization of complete dentures in Controlled Diabetic patients. Material & Methods: This study included thirty completely edentulous well controlled diabetic patients which were divided into two equal groups, fifteen patients received complete dentures made of conventional heat cured acrylic resin dentures while the other fifteen patients received upper complete denture made of flexible poly amide (Bre-flex 2ndedtion) thermoplastic dentures and lower heat cured acrylic resin denture. Oral swabs for isolation of microorganisms was done with gamma sterilized disposable swabs from tuberosity area under the fitting surface of the dentures, each swab cultivated in three culture media. Statistical analysis was performed for the results of this study to evaluate the microbial colonization in each of the two groups. Results: Candida was the most common isolate in acrylic resin group and was detected in 6 cases (40%) and Streptococci were observed in 3 cases (20%). Chi square test revealed a significant difference in the percentage of Candida species were the most common isolate in breflex group and were detected in 3 cases (20%). Staph Aureus and Streptococci were observed in 2 cases each (13%). Chi square test revealed a significant difference in the percentage of cases affecting by each type of microorganisms (p<0.00001).cases affecting by each type of microorganisms by Cfu (ml)x102. Conclusion: Flexible thermoplastic resin denture is thus a more predictable treatment modality as a denture base material due to its less microbial colonization and biological reaction in addition to its better esthetic appearance.