BACKGROUND: Clostridium difficile is the most common health care-associated infection. Despite considerable efforts to prevent and manage C difficile, poor clinical practice and nonadherence to policy continues to compromise patient safety. Risk perception research is essential in gaining understanding about how health care professionals respond. METHODS: A structured literature review examined empirical evidence regarding health care professionals' risk perceptions and responses toward C difficile. Because of limited evidence available, the review was extended to include other health care-associated infections. Only studies related to methicillin-resistant Staphylococcus aureus (MRSA) could be identified. RESULTS: Eleven studies were included. Four were specific to C difficile and 7 to MRSA. All studies found that technical understanding of C difficile was poor and that staff were concerned about risks to patients and themselves. Technical understanding for MRSA, however, was good, and staff were less concerned about their own health. Information provision was perceived to be inadequate and untrustworthy, which included the media. Practice in most studies was poor. CONCLUSION: There is a need to build on the efforts of risk perception research from other disciplines to understand how health care professionals think and make decisions about C difficile. This can help inform the development of effective management and communication strategies to maximize the quality of care provided.