Clostridium difficile and Clostridium perfringens are among the most commonagents of enteric disease in both humans and domestic animals. The former continues to increase in prevalence and diseases caused by the latter persist. Infection with a recently emergedhypervirulent strain (NAP1/027/III) of C. difficile is increasingly common andserious sequelae and fatalities are much more common in these patients. In neonatalpiglets, C. difficile infection (CDI) has become a common occurrence. Historically,isolation of C. perfringens type A from patients with enteric disease has been consideredinconsequential due to its presence in the normal intestine and to the mild nature ofdisease syndromes such as porcine enteritis. However, both CDI and type A diseasecause losses to the swine industry and pigs have been implicated as a possible source ofC. difficile for infection in humans. We investigated the epidemiology and pathogenesisof porcine CDI, and immunity against porcine CDI and type A enteritis. The occurrenceof CDI in integrated swine production facilities was most common in neonatal pigs.Infection in sows was rare, and finisher pigs were culture negative. All C. difficile strainswere ribotype 078. Hypervirulent strain NAP1/027/TTIII was more virulent in neonatalpigs than both a historic human historic human strain and a porcine strain with toxinproducing potential similar to ribotype 027 strains. Inoculation of anti-microbial-treatedadolescent pigs with NAP1/027/III did not cause disease. Ingra-gastric inoculation ofpigs with purified TcdA resulted in severe small intestine damage which isuncharacteristic of natural disease; effects of TcdB were minimal. Passive immunizationof piglets against C. difficile TcdA or C. perfringens type A alpha (CPA) and beta 2(CPB2) toxins did not prevent disease.