Objective: To measure the neonatal mortality rate (NMR) and investigate its predictors in a rural area of Burkina Faso. Study Design: A cohort of infants born in 24 villages in Banfora region was followed until the children were 6 months old. We estimated the risk of neonatal death and used logistic regression to identify its predictors. Result: Among 864 live births followed to day 28, there were 40 neonatal deaths, a NMR of 46.3 per 1000 live births (95% confidence intervals (CI): 22 to 70). Multivariable regression identified twin birth (OR=11.5, 95%CI: 4.5 to 29.8), having a nulliparous mother (odds ratio (OR)=4.3, 95% CI: 1.5 to 12.1), and birth into a polygynous household (OR=2.1, 95% CI: 1.0 to 4.7) as main predictors of neonatal death. Conclusion: The burden of neonatal mortality in rural Burkina Faso is very high and the observed NMRs in a predominantly rural country suggest that it is unlikely Burkina will meet fourth Millennium Development Goal (MDG-4) by 2015.