Healthcare-associated infections (HCAIs) continue to be a challenge in developed and developing countries. Hand hygiene practice is considered to be the most effective strategy to prevent HCAIs, but healthcare workers’ compliance is poor. Using a human factors perspective, this learning module explores elements that affect healthcare workers’ hand hygiene compliance. Slips, lapses and mistakes can occur depending on the worker’s skills and knowledge levels. Violations of protocols may also occur, and these may be associated with the intention to provide care efficiently. Strong leadership and an understanding of why non-compliance with hand hygiene occurs assists with developing strategies to improve compliance.