Background A third of people may experience persistent symptoms following COVID-19. With over 90% of South Africans having evidence of prior SARS-CoV-2 infection, it is likely that many people could be affected by Post COVID-19 Condition (PCC). Methods This was a prospective, longitudinal observational cohort study recruiting hospitalised and non-hospitalised participants, infected during the periods that Beta, Delta and Omicron BA.1 variants dominated in South Africa. Participants aged 18 years or older were randomly selected to undergo telephone assessment at 1, 3 and 6 months after hospital discharge or laboratory-confirmed SARS-CoV-2 infection. Participants were assessed using a standardised questionnaire for evaluation of symptoms and health-related quality of life. We used negative binomial regression models to determine factors associated with the presence of 1 or more symptoms at 6 months. Findings Among hospitalised and non-hospitalised participants, 46.7% (1,227/2,626) and 18.5% (199/1,074) had 1 or more symptoms at 6 months (p=<0.001). Among hospitalised participants 59.5%, 61.2% and 18.5% experienced symptoms at 6 months among individuals infected during the Beta, Delta and Omicron dominant waves respectively. Among PLWH who were hospitalised, 40.4% had symptoms at 6 months compared to 47.1% among HIV-uninfected participants (p=0.108). Risk factors for PCC included older age, female sex, non-black race, the presence of a comorbidity, greater number of acute COVID-19 symptoms, hospitalisation/ COVID-19 severity and wave period (individuals infected during the Omicron-dominated wave had a lower risk of persistent symptoms [adjusted Incident Risk Ratio 0.45; 95% Confidence Interval 0.36-0.57] compared to those infected during the Beta-dominated wave). There were no associations between self-reported vaccination status before or after SARS-CoV-2 infection with persistent symptoms. Interpretation The study revealed a high prevalence of persistent symptoms among South African participants at 6 months although decreased risk for PCC among participants infected during the Omicron BA.1 wave. These findings have serious implications for countries with resource-constrained healthcare systems. Funding Bill & Melinda Gates Foundation, UK Foreign, Commonwealth & Development Office, and Wellcome.