BACKGROUND: Child mortality has decreased considerably in recent years but more than one in ten children still die before their fifth birthday in several African countries. The MORDOR study investigated whether azithromycin mass drug administration (MDA) reduces child mortality in three countries in Africa. The study described within this thesis was conducted at the MORDOR-Malawi site and aims to provide additional detail on potential mechanisms of effect of the intervention; macrolide resistance; and cost-effectiveness. METHODS: The study involved cluster randomisation of communities in Mangochi District, Malawi, to biannual azithromycin or placebo MDA. Household visits were conducted to update the census and perform verbal autopsies (VAs) to assess causes of death. Indicators related to healthcare access; malaria risk; and water, sanitation and hygiene were measured. Nasopharyngeal samples were collected to assess macrolide resistance. Cost data were collected for one complete round of fieldwork. RESULTS: The study included 334 clusters. The mortality rate ratio in azithromycin-treated compared to placebo-treated communities was 0.91 (95%CI: 0.79–1.05); P=0.20. There was evidence for an effect of the intervention in infants aged 1-5 months: 0.70 (95%CI: 0.50-0.99); P=0.04; but not in older age groups. The VA analyses suggested possible effects on pneumonia, HIV/AIDS and diarrhoea mortality. The intervention was highly cost-effective according to the WHO’s willingness-to-pay thresholds, costing $898 per death averted. At the 12-month and 24-month follow-up rounds, macrolide resistance in Streptococcus pneumoniae was higher in the azithromycin group compared to placebo. CONCLUSION: The mortality findings at the MORDOR-Malawi site could be explained by the broad spectrum of activity of azithromycin against gut and respiratory organisms, including non-vaccine pneumococcal serotypes and other aetiological causes of pneumonia, sepsis and meningitis. Azithromycin MDA is a feasible short-term intervention to reduce child mortality, whilst longer term sustainable health system improvements are pursued. Vigilance of antibiotic resistance is required.