To investigate risk factors for healthcare worker (HCW) infection in viral respiratory pandemics: severe acute respiratory coronavirus virus 2 (SARS-CoV-2), Middle East respiratory syndrome (MERS), SARS CoV-1, influenza A H1N1, influenza H5N1. To improve understanding of HCW risk management amid the COVID-19 pandemic. Systematic review and meta-analysis. We searched MEDLINE, EMBASE, CINAHL, and Cochrane CENTRAL databases from conception until July 2020 for studies comparing infected HCWs (cases) and noninfected HCWs (controls) and risk factors for infection. Outcomes included HCW types, infection prevention practices, and medical procedures. Pooled effect estimates with pathogen-specific stratified meta-analysis and inverse variance meta-regression analysis were completed. We used the GRADE framework to rate certainty of evidence. (PROSPERO no. CRD42020176232, 6 April 2020.). In total, 54 comparative studies were included (n = 191,004 HCWs). Compared to nonfrontline HCWs, frontline HCWs were at increased infection risk (OR, 1.66; 95% CI, 1.24-2.22), and the risk was greater for HCWs involved in endotracheal intubations (risk difference, 35.2%; 95% CI, 21.4-47.9). Use of gloves, gown, surgical mask, N95 respirator, face protection, and infection training were each strongly protective against infection. Meta-regression showed reduced infection risk in frontline HCWs working in facilities with infection designated wards (OR, -1.04; 95% CI, -1.53 to -0.33, P = .004) and performing aerosol-generating medical procedures in designated centers (OR, -1.30; 95% CI, -2.52 to -0.08; P = .037). During highly infectious respiratory pandemics, widely available protective measures such as use of gloves, gowns, and face masks are strongly protective against infection and should be instituted, preferably in dedicated settings, to protect frontline HCW during waves of respiratory virus pandemics.