Clostridium difficile infection (CDI) is the most common cause of antibiotic-associated diarrhea and a significant burden on the health care system. Aging has been identified in the literature as a risk factor for CDI as well as adverse outcome from CDI. Although this effect of advanced age on CDI could be partially explained by clinical factors associated with aging, biologic factors are important. Innate immune system, responsible for immediate response to acute infections, plays a major role in CDI pathogenesis. Impairment in function of innate immunity with aging, demonstrated in other infection models, may lead to worse outcome with CDI. C. difficile toxin-specific antibody response protects the host against initial and recurrent infections as shown in observational studies and clinical trial. Effect of aging on antibody response to CDI has not been demonstrated, but the results from vaccine studies in other infections suggest a negative effect on humoral immunity from aging. Although intestinal microbiota from healthy people confers resistance to CDI by preventing C. difficile colonization, changes in composition of microbiota with aging may affect that resistance and increase risk for CDI. There are also age-associated changes in physiology, especially of the gastrointestinal tract, that may play a role in CDI risk and outcomes. In this review, we will first discuss the epidemiology of CDI in the elderly people, then the alteration in innate immunity, humoral response, and microbiota that increases susceptibility to CDI and severe disease and lastly, the physiological and functional changes that may modify outcomes of infection.