Previous surveys of infectious diseases specialists conducted by the Infectious Diseases Society of America through its Emerging Infections Network noted an increase in frequency, severity, and recalcitrant or recurrent Clostridium difficile infection (CDI) from 2003 to 2004. The Clostridium difficile Surveillance Project was launched in October 2005 to continue to examine the experience with CDI of clinicians worldwide. Health care practitioners who treat patients with CDI were invited to complete a Web-based survey about the global management of CDI over the preceding 12-month period. As of December 31, 2007, 1976 unique clinicians reported an increased caseload, more severe cases, and increased relapses after treatment. Respondents from the US region of North America observed almost twice as many patients with severe CDI (52%) compared with respondents from Asia and South America (27% and 29%, respectively; P < 0.0001), where colectomies and mortality were also lower. The severity and frequency of CDI continued to increase through 2005 to 2007; however, most respondents could not confirm the presence of the current epidemic strain in their institutions. Continued surveillance of this re-emerging infection and increased efforts to culture stools and perform typing to identify the causative C. difficile organisms seem warranted.