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Background Acquisition of a health care–associated infection is a substantial risk to patient safety. When health care workers comply with hand hygiene guidelines, it reduces this risk. Despite a growing body of qualitative research in this area, a review of the qualitative literature has not been published. Methods A systematic review of the qualitative literature. Results The results were themed by the factors that health care workers identified as contributing to their compliance with hand hygiene guidelines. Contributing factors were conceptualized using a theoretical background. This review of the qualitative literature enabled the researchers to take an inductive approach allowing for all factors affecting the phenomenon of interest to be explored. Two core concepts seem to influence health care workers' compliance with hand hygiene guidelines. These are motivational factors and perceptions of the work environment. Motivational factors are grounded in behaviorism, and the way in which employees perceive their work environment relates to structural empowerment. Conclusion Noncompliance with hand hygiene guidelines remains a collective challenge that requires researchers to adopt a consistent and standardized approach. Theoretical models should be used intentionally to better explain the complexities of hand hygiene.