OBJECTIVES: Our study described demographic characteristics, exposures and symptoms, and comorbidities to evaluate risk factors of hospitalisation and mortality among cases in Juba, South Sudan (SSD) and North and South Kivu in eastern Democratic Republic of the Congo (DRC). DESIGN: Prospective observational cohort of COVID-19 cases. METHODS: Individuals presenting for care at one of five study facilities in SSD (n=1) or DRC (n=4) or referred from home-based care by mobile medical teams between December 2020 and June 2021 were eligible for enrolment. Demographic characteristics, COVID-19 exposures, symptoms at presentation, as well as acute and chronic comorbidities, were evaluated using a standard questionnaire at enrolment. Disease progression was characterised by location of care using mixed-effects regression models. RESULTS: 751 individuals were eligible for enrolment. Among cases followed to discharge or death (n=519), 375 were enrolled outpatients (75.7%). A similar number of cases were enrolled in DRC (n=262) and SSD (n=257). Overall mortality was 4.8% (95% CI: 3.2% to 6.9%); there were no outpatient deaths. Patients presenting with any symptoms had higher odds of hospitalisation (adjusted OR (AOR) 2.78, 95% CI 1.47 to 5.27) and all deaths occurred among symptomatic individuals. Odds of both hospitalisation and mortality were greatest among cases with respiratory symptoms; presence of low oxygen levels on enrolment was strongly associated with both hospitalisation (AOR 7.77, 95% CI 4.22 to 14.29) and mortality (AOR 25.29, 95% CI 6.42 to 99.54). Presence of more than one chronic comorbidity was associated with 4.96 (95% CI 1.51 to 16.31) times greater odds of death; neither infectious comorbidities evaluated, nor malnutrition, were significantly associated with increased mortality. CONCLUSIONS: Consistent with prior literature, older age, low oxygen level, other respiratory symptoms and chronic comorbidities were all risk factors for mortality. Patients presenting with these characteristics were more likely to be hospitalised, providing evidence of effective triage and referral. TRIAL REGISTRATION NUMBER: NCT04568499.