Clostridioides difficile is the cause of the C. difficile infection (CDI) in humans and several other animal species. The microorganism is also found in the environment and in the gastrointestinal tract of healthy individuals of multiple animals of a variety of species. Although CDI in most domestic animals has historically been described in individuals receiving antibiotic treatment, or in the case of horse, hospitalized animals, the number of cases in which no antibiotic treatment or hospitalization association was known has been increasing over the past few years. Co-infections with other bacteria or parasites, intestinal displacements, transport, or surgical or medical treatment are also possible predisposing factors for CDI in horses. In most animals species, CDI is not age-associated. Although it has been suggested that CDI may be a zoonosis, this has not been demonstrated.