BACKGROUND: Health care-associated infections affect hundreds of millions of patients worldwide each year. The World Health Organization's (WHO) First Global Patient Safety Challenge, "Clean Care is Safer Care," is tackling this major patient safety problem, with the promotion of hand hygiene in health care as the project's cornerstone. WHO Guidelines on Hand Hygiene in Healthcare have been prepared by a large group of international experts and are currently in a pilot-test phase to assess feasibility and acceptability in different health care settings worldwide. METHODS: An extensive literature search was conducted and experts and religious authorities were consulted to investigate religiocultural factors that may potentially influence hand hygiene promotion, offer possible solutions, and suggest areas for future research. RESULTS: Religious faith and culture can strongly influence hand hygiene behavior in health care workers and potentially affect compliance with best practices. Interesting data were retrieved on specific indications for hand cleansing according to the 7 main religions worldwide, interpretation of hand gestures, the concept of "visibly dirty" hands, and the use of alcohol-based hand rubs and prohibition of alcohol use by some religions. CONCLUSIONS: The impact of religious faith and cultural specificities must be taken into consideration when implementing a multimodal strategy to promote hand hygiene on a global scale.