Personal protective equipment (PPE) is a critical aspect of preventing the transmission of severe acute respiratory coronavirus virus 2 (SARS-CoV-2) in healthcare settings. We aimed to identify factors related to lapses in PPE use that may influence transmission of SARS-CoV-2 from patients to healthcare personnel (HCP). Retrospective cohort study. Tertiary-care medical center in Minnesota. In total, 345 HCP who sustained a significant occupational exposure to a patient with coronavirus disease 2019 (COVID-19) from May 13, 2020, through November 30, 2020, were evaluated. Overall, 8 HCP (2.3%) were found to have SARS-CoV-2 infection during their 14-day postexposure quarantine. A lack of eye protection during the care of a patient with COVID-19 was associated with HCP testing positive for SARS-CoV-2 by reverse-transcriptase polymerase chain reaction (RT-PCR) during the postexposure quarantine (relative risk RR, 10.25; 95% confidence interval CI, 1.28-82.39; = .009). Overall, the most common reason for a significant exposure was the use of a surgical face mask instead of a respirator during an aerosol-generating procedure (55.9%). However, this was not associated with HCP testing positive for SARS-CoV-2 during the postexposure quarantine (RR, 0.99; 95% CI, 0.96-1; = 1). Notably, transmission primarily occurred in units that did not regularly care for patients with COVID-19. The use of universal eye protection is a critical aspect of PPE to prevent patient-to-HCP transmission of SARS-CoV-2.