Management of cancers of oral cancers has remained a major challenge in India and globally. Radiotherapy and chemotherapy are mostly employed for treatment which inflicts changes in oral mucosa and makes it vulnerable for bacterial colonization and eventual infections. This study aims at evaluating the changes in oropharyngeal flora (bacteria and yeast) in oral cancer patients treated by a combination of chemo-radiotherapy with the control groups comprising of non-cancerous patients living in the same environment. This prospective evaluation included Seventy-seven patients with oral squamous cell carcinomas in the study group. Whereas the control group comprised of twenty-five non-cancerous patients. Saliva samples were collected from patients with oral carcinomas and those of the control group for bacteriological examination, and were transported within 2 hours to the laboratory and immediately inoculated and incubated. The oral microflora samples collected were evaluated for the presence of bacteria in saliva in both study and control group of patients. We evaluated the change in salivary oral flora during chemo-radiotherapy treatment. A statistically significant increase in growth of normal as well as abnormal oral flora was observed post-radiation. Escherichia coli showed a significant decrease in post-RT and also near to significant in control. Various changes in salivary oral flora were observed during the course of chemo-radiotherapy in study and controls groups. This shows that there are some sensitive spots in the oral cavity where the occurrence of oral cancer is more.