Respiratory disease is the predominant cause of illness in children globally. We describe a unique multidisciplinary South African birth cohort, the Drakenstein Child Health Study (DCHS), to investigate the incidence, risk factors, aetiology and long-term impact of early lower respiratory tract infection (LRTI) on child health. Pregnant women from a poor, peri-urban community with high exposure to infectious diseases and environmental risk factors are enrolled with 1000 mother–child pairs followed for at least 5 years. Biomedical, environmental, psychosocial and demographic risk factors are longitudinally measured. Environmental exposures are measured using monitors placed at home visits. Lung function is measured in children at 6 weeks, annually and during LRTI episodes. Microbiological investigations including microbiome and multiplex PCR measures are done longitudinally and at LRTI episodes. The DCHS is a unique African birth cohort study that uses sophisticated measures to comprehensively investigate the early-life determinants of child health in an impoverished area of the world.