Childhood mortality in Upper River Division, The Gambia is high, 99 per 1000 mid-year population, and 27% of deaths occur is the neonatal period. The aims of the present study were to describe patterns of neonatal death and to identify risk factors. Cause of death was investigated using a neonatal post-mortem questionnaire, and a population-based, matched case-control study was conducted to identify potential risk factors. The neonatal mortality rate in Upper River Division was 39 per 1000 live births (95% CI 36.8-41.2). The rates in the early and late neonatal periods were 21.0 (19.4-22.6) and 18.0 (16.5-19.5), respectively. Infection accounted for 57% of all deaths. In the early neonatal period, 30% of deaths were due to prematurity. Only 55% of babies who died presented for treatment and 84% died at home. Risk factors for neonatal death were primiparity (OR 2.18), previous stillbirth (OR 3.19), prolonged labour (OR 2.80) and pre-lacteal feeding (OR 3.38). A protective effect was seen in association with delivery by a trained traditional birth attendant (OR 0.34) and the application of shea nut butter, a traditional medicine, to the cord stump (OR 0.07). This study has identified the need to understand the reasons underlying the widespread use of pre-lacteal feeds and the barriers to health service use in this community in order to plan effective interventions.