Background: Healthcare workers (HCWs) in close contact with SARS-CoV-2-infected patients have an increased risk of infection compared to non-HCWs, but little is known about the clinical course and risks for mortality amongst HCWs in South Africa. In this study, we compared characteristics of hospitalised HCWs with non-HCWs with COVID-19 and assessed factors associated with COVID-19 mortality among HCWs. Methods: Data from 5 March 2020 to 30 April 2021 was obtained from DATCOV, the national surveillance programme monitoring COVID-19 admissions in private and public hospitals across South Africa. A logistic regression model was used to determine factors associated with COVID-19 HCW admissions and mortality.Results: There were a total 169,678 confirmed COVID-19 admissions reported on DATCOV, of which 6,364 (3.8%) were HCWs. Compared to non-HCWs, HCWs were less likely to be male [aOR 0.3, 95%CI (0.3-0.4)], and more likely to be younger, white or other race, have pre-existing obesity and asthma, and be admitted in the private sector, in Eastern Cape, Gauteng, Kwa-Zulu Natal, Limpopo, Northern Cape and North West provinces. Pre-wave 1 [aOR 3.0; 95%CI 2.4-3.7)], wave 1 [aOR 2.1; 95%CI (1.8-2.5)] and post-wave 1 [aOR 1.3; 95%CI (1.0-1.7)] were associated with increase in HCW admissions compared to wave 2. There was an increased risk for in-hospital mortality among HCWs in the older age group (40-49 [aOR 3.8; 95%CI (1.6-8.80)]; 50-59 [aOR 4.7; 95%CI (2.0-10.9)] and 60-65 years [aOR 9.8; 95%CI (4.2-23.0)] compared to HCWs less than 40 years, with comorbidities such as hypertension, diabetes, chronic kidney diseases, malignancy and TB. Mortality was decreased for HCWs who were coloured [aOR 0.5; 95%CI (0.3-0.8)], admitted in the public sector [aOR 0.7; 95%CI (0.5-0.9)] in pre-wave 1 [aOR 0.6; 95%CI (0.3-0.9)] compared to wave one period. Conclusion: In-hospital mortality in HCWs was associated with age, race, wave period, presence of comorbidites and sector. Policies should be put in place to remove older HCWs with comorbidities from direct patient care. Optimal management of comorbid conditions is advised and improvement of infection prevention and control measures in healthcare settings for those that come into direct contact with infected patients.