BACKGROUND: People experiencing homelessness are among the most socially and medically vulnerable populations OBJECTIVES: To assess the prevalence of comorbid disease and associated risk factors among homeless people admitted to temporary shelters in the City of Tshwane during levels 4 and 5 of the COVID-19 national lockdown in South Africa. METHODS: A descriptive cross-sectional study design was used. The sample was drawn from secondary data on all individuals placed in temporary shelters constructed by Tshwane during levels 4 and 5 of the COVID-19 lockdown (26 March - 31 May 2020). Descriptive statistics were used to summarise data, and a multivariable logistic regression model was applied to determine factors associated with comorbid disease RESULTS: The overall prevalence of comorbid disease among homeless people in temporary shelters in Tshwane was 28.8% (95% confidence interval (CI) 26.9 - 30.8). There was no significant difference in the prevalence of comorbid disease by illicit substance use (29.9% for users v. 29.5% for non-users; p=0.871). In adjusted analyses, being South African (adjusted odds ratio (aOR) 2.06; 95% CI 1.10 - 3.88; p=0.024), being female (aOR 3.73; 95% CI 1.85 - 7.53; p<0.001), being black (aOR 3.43; 95% CI 1.12 - 10.54; p=0.031) or white (aOR 6.11; 95% CI 1.55 - 24.0; p=0.01), and injecting substances (aOR 1.68; 95% CI 1.19 - 2.37; p=0.003) were significantly associated with having comorbid disease CONCLUSION: The study found a 28.8% prevalence of comorbid disease among homeless people placed in temporary shelters in Tshwane. In adjusted analysis, being South African, being female, black and white race, and injecting substances were associated with having comorbid disease. Strengthening of public health interventions such as needle and syringe exchange programmes, family planning and access to primary care with health education could improve the healthcare of people experiencing homelessness