Limited data exists on the epidemiology of C. difficile with either colorectal cancer or early colonic lesions (polyps). Additionally, whether protumorigenic signaling events occur in patient specimens colonized with C. difficile remains completely unknown. Finally, whether C. difficile’s toxin TcdB promotes cancer-causing mutations directly or indirectly remains unclear. Our proposal seeks to lay the foundation for answering these critical questions using a combination of clinical samples from a large screening colonoscopy cohort as well as in vitro and animal models. These studies could have immediate implications for both short-term and long-term follow-up care for C. difficile-infected patients; for example, informing whether more frequent colonoscopies would be beneficial for these patients.