Highly virulent strains of Clostridium difficile have emerged since 2003, causing large outbreaks of severe, often fatal, colitis in North America and Europe. In 2008–10, virulent strains spread between continents, with the first reported cases of fluoroquinolone-resistant C difficile PCR ribotype 027 in three Asia-Pacific countries and Central America. We present a risk assessment framework for assessing risks of further worldwide spread of this pathogen. This framework first requires identification of potential vehicles of introduction, including international transfers of hospital patients, international tourism and migration, and trade in livestock, associated commodities, and foodstuffs. It then calls for assessment of the risks of pathogen release, of exposure of individuals if release happens, and of resulting outbreaks. Health departments in countries unaffected by outbreaks should assess the risk of introduction or reintroduction of C difficile PCR ribotype 027 using a structured risk-assessment approach.