This study describes the characteristics of admitted HCWs reported to the DATCOV surveillance system, and the factors associated with in-hospital mortality in South African HCWs. Data from March 5, 2020 to April 30, 2021 were obtained from DATCOV, a national hospital surveillance system monitoring COVID-19 admissions in South Africa. Characteristics of HCWs were compared with those of non-HCWs. Furthermore, a logistic regression model was used to assess factors associated with in-hospital mortality among HCWs. In total, there were 169 678 confirmed COVID-19 admissions, of which 6364 (3.8%) were HCWs. More of these HCW admissions were accounted for in wave 1 (48.6%; n = 3095) than in wave 2 (32.0%; n = 2036). Admitted HCWs were less likely to be male (28.2%; n = 1791) (aOR 0.3; 95% CI 0.3-0.4), in the 50-59 age group (33.1%; n = 2103) (aOR 1.4; 95% CI 1.1-1.8), or accessing the private health sector (63.3%; n = 4030) (aOR 1.3; 95% CI 1.1-1.5). Age, comorbidities, race, wave, province, and sector were significant risk factors for COVID-19-related mortality. The trends in cases showed a decline in HCW admissions in wave 2 compared with wave 1. Acquired SARS-COV-2 immunity from prior infection may have been a reason for reduced admissions and mortality of HCWs despite the more transmissible and more severe beta variant in wave 2.