Clostridium difficile infections (CDIs) are the number one cause of hospital-acquired diarrhea in the United States. Several clinical studies have reported higher incidence and severity of CDI in patients with one of the two major forms of inflammatory bowel disease (IBD): ulcerative colitis and Crohn’s disease. In order to understand the factors underlying increased severity of CDI in IBD patients, we utilized a Dextran Sulfate Sodium (DSS) murine model of inflammatory colitis. In support of clinical observations, our data showed that mice treated with DSS and then infected with C. difficile developed a more severe C. difficile disease compared to untreated mice. Increased severity of disease was measured by increased mortality, weight loss and clinical score. Importantly, comparison of C. difficile burden between mice with prior DSS colitis and untreated controls showed no differences in C. difficile colonization between the two groups, suggesting that increased severity of disease might be due to the host immune response to infection. Immunophenotyping of immune cells recruited to the colon at the peak of CDI revealed increased levels of CD4+ T cells at the site of infection in mice with prior DSS colitis. Furthermore, depletion of CD4+ T cells using a monoclonal antibody protected mice with prior DSS colitis from severe C. difficile disease. These data have identified a novel role for CD4+ T cells in contributing to increased severity of CDI. Our current studies are aimed at understanding the downstream mechanisms by which these T cells are acting to drive severe CDI disease.