BACKGROUND: Reducing neonatal mortality rates (NMR) in developing countries is a key global health goal, but weak registration systems in the region stifle public health efforts. OBJECTIVE: To calculate NMRs, investigate modifiable risk factors, and explore neonatal deaths by place of birth and death, and cause of death in two administrative areas in Ghana. METHODS: Data on livebirths were extracted from the health and demographic surveillance systems in Navrongo (2004-2012) and Kintampo (2005-2010). Cause of death was determined from neonatal verbal autopsy forms. Univariable and multivariable logistic regression were used to analyse factors associated with neonatal death. Multiple imputations were used to address missing data. RESULTS: The overall NMR was 18.8 in Navrongo (17,016 live births, 320 deaths) and 12.5 in Kintampo (11,207 live births, 140 deaths). The annual NMR declined in both areas. 54.7% of the births occurred in health facilities. 70.9% of deaths occurred in the first week. The main causes of death were infection (NMR 4.3), asphyxia (NMR 3.7) and prematurity (NMR 2.2). The risk of death was higher among hospital births than home births: Navrongo (adjusted OR 1.14, 95% CI: 1.03-1.25, p = 0.01); Kintampo (adjusted OR 1.76, 95% CI: 1.55-2.00, p < 0.01). However, a majority of deaths occurred at home (Navrongo 61.3%; Kintampo 50.7%). Among hospital births dying in hospital, the leading cause of death was asphyxia; among hospital and home births dying at home, it was infection. CONCLUSION: The NMR in these two areas of Ghana reduced over time. Preventing deaths by asphyxia and infection should be prioritised, centred respectively on improving post-delivery care in health facilities and subsequent post-natal care at home.