BACKGROUND: Healthcare workers (HCWs) are at particular risk during pandemics and epidemics of highly virulent diseases with significant morbidity and case fatality rate. These diseases include severe acute respiratory syndrome coronaviruses, SARS-CoV-1 and SARS-CoV-2, Middle Eastern Respiratory Syndrome (MERS), and Ebola. With the current (SARS-CoV-2) global pandemic, it is critical to delineate appropriate contextual respiratory protection for HCWs. The aim of this systematic review was to evaluate the effect of powered air-purifying respirators (PAPRs) as part of respiratory protection versus another device (egN95/FFP2) on HCW infection rates and contamination. METHODS: Our primary outcomes included HCW infection rates with SARS-CoV-2, SARS-CoV-1, Ebola, or MERS when utilizing PAPR. We included randomized controlled trials, non-randomized controlled trials, and observational studies. We searched the following databases: MEDLINE, EMBASE, and Cochrane Library (Cochrane Database of Systematic Reviews and CENTRAL). Two reviewers independently screened all citations, full-text articles, and abstracted data. Due to clinical and methodological heterogeneity, we did not conduct a meta-analysis. Where applicable, we constructed evidence profile (EP) tables for each individual outcome. Confidence in cumulative evidence for each outcome was classified according to the GRADE system. RESULTS: We identified 689 studies during literature searches. We included 10 full-text studies. A narrative synthesis was provided. Two on-field studies reported no difference in the rates of healthcare workers performing airway procedures during the care of critical patients with SARS-CoV-2. A single simulation trial reported a lower level of cross-contamination of participants using PAPR compared to alternative respiratory protection. There is moderate quality evidence that PAPR use is associated with greater heat tolerance but lower scores for mobility and communication ability. We identified a trend towards greater self-reported wearer comfort with PAPR technology in low-quality observational simulation studies. CONCLUSION: Field observational studies do not indicate a difference in healthcare worker infection utilizing PAPR devices versus other compliant respiratory equipment. Greater heat tolerance accompanied by lower scores of mobility and audibility in PAPR was identified. Further pragmatic studies are needed in order to delineate actual effectiveness and provider satisfaction with PAPR technology. SYSTEMATIC REVIEW REGISTRATION: The protocol for this review was prospectively registered with the International Register of Systematic Reviews identification number CRD42020184724 .