Immunotherapy with checkpoint inhibitors (ICI) is widely used to treat a variety of neoplasms. ICI can induce an immune response against cancer; however, ICI can also induce autoimmunity, an undesirable side effect. Autoimmune colitis is one of the most well-known and troubling side effects of ICI. In this report, we described a series of 5 patients who developed ICI-induced colitis. During the course of this complication, all developed Clostridium difficile infection (CDI). This report described the course of the 2 medical conditions in these patients. On the basis of our experiences, CDI may occur as a superimposed infection during ICI-induced colitis. Although ICI-induced colitis may be a risk factor for CDI, the observed association may be fortuitous. Future study will be needed to characterize the association between CDI and ICI-induced colitis. Clinicians should be mindful of possible co-occurrence of both conditions to promptly and adequately institute effective interventions.