Background: Clostridium difficile (C.difficile) is the most common healthcare associated infection. Despite considerable efforts to prevent and manage C.difficile, poor clinical practice and non-adherence to policy continues to compromise patient safety. Risk perception research is essential in gaining understanding about how healthcare professionals respond. Methods: A structured literature review examined empirical evidence regarding healthcare professionals’ risk perceptions and responses towards C.difficile. Due to limited evidence available, the review was extended to include other healthcare associated infections. Only studies related to MRSA could be identified. Results: Eleven studies were included. Four were specific to C.difficile and 7 to MRSA. All studies found technical understanding of C.difficile was poor and 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. Conclusions: There is a need to build on the efforts of risk perception research from other disciplines to understand how healthcare professionals think and make decisions about C.difficile. This can help inform the development of effective management and communication strategies to maximise the quality of care provided.