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Peri- and neonatal mortality remain high in developing countries, especially in sub-Saharan Africa. In the present study, we quantified and identified the most important predictors of early mortality in rural Malawi. Data were obtained from a community-based cohort of 795 pregnant women and their 813 fetuses, followed prospectively from mid-pregnancy. In this group, peri- and neonatal mortality rates were 65.3 deaths per 1000 births and 37.0 deaths per 1000 live births respectively. When controlled for month of birth, maternal age and selected socio-economic variables, preterm birth was the strongest independent predictor of both peri- and neonatal mortality (adjusted odds ratios 9.6 for perinatal and 11.0 for neonatal mortality; 95% confidence intervals: [4.4, 21.0] and [3.7, 32.7] respectively). Weaker risk factors for mortality included a maternal history of stillbirth and abnormal delivery. Preterm delivery was associated with primiparity and peripheral malaria parasitaemia of the mother, and it accounted for 65% of the population-attributable risk for perinatal and 68% of the neonatal mortality. Successful intervention programmes to reduce peri- and neonatal mortality in Malawi have to include strategies to predict and prevent prematurity.