Background: There is general consensus that hand hygiene is the most effective way to prevent healthcare-associated infections. However, low rates of compliance amongst healthcare workers have been reported globally. The coronavirus disease 2019 pandemic has further emphasized the need for global improvement in hand hygiene compliance by healthcare workers. Aim: This comprehensive systematic review provides an up-to-date compilation of clinical trials, reported between 2014 and 2020, assessing hand hygiene interventions in order to inform healthcare leaders and practitioners regarding approaches to reduce healthcareassociated infections using hand hygiene. Methods: CINAHL, Cochrane, EMbase, Medline, PubMed and Web of Science databases were searched for clinical trials published between March 2014 and December 2020 on the topic of hand hygiene compliance among healthcare workers. In total, 332 papers were identified from these searches, of which 57 studies met the inclusion criteria. Findings: Forty-five of the 57 studies (79%) included in this review were conducted in Asia, Europe and the USA. The large majority of these clinical trials were conducted in acute care facilities, including hospital wards and intensive care facilities. Nurses represented the largest group of healthcare workers studied (44 studies, 77%), followed by physicians (41 studies, 72%). Thirty-six studies (63%) adopted the World Health Organization's multimodal framework or a variation of this framework, and many of them recorded hand hygiene opportunities at each of the 'Five Moments'. However, recording of hand hygiene technique was not common. Conclusion: Both single intervention and multi-modal hand hygiene strategies can achieve modest-to-moderate improvements in hand hygiene compliance among healthcare workers.