C. diphtheriae has shown to exclusively infect humans. It is believed that humans may be the reservoir for this pathogen. However, there have been extremely rare cases in which C. diphtheriae has been found in animals. These infections were only toxigenic in two dogs and two horses.

The disease occurs primarily in tropical regions and developing countries. Immunocompromised individuals, poorly immunized adults, and unvaccinated children are at the greatest risk of contracting diphtheria.