Even though ventilator technology and monitoring of premature infants has improved immensely over the past decades, there are still no standards for weaning and determining optimal extubation time for those infants. Approximately 30% of intubated preterm infants will fail attempted extubation, requiring reintubation and resuming of mechanical ventilation. A machine-learning approach using artificial neural networks (ANNs) to aid in extubation decision making is hereby proposed. Using expert opinion, 51 variables were identified as being relevant for the decision of whether to extubate an infant who is on mechanical ventilation. The data on 183 premature infants, born between 1999 and 2002, were collected by review of medical charts. The ANN extubation model was compared with alternative statistical modeling using multivariate logistic regression and also with the clinician's own predictive insight using sensitivity analysis and receiver operating characteristic curves. The optimal ANN model used 13 parameters and achieved an area under the receiver operating characteristic curve of 0.87 (out-of-sample validation), comparing favorably with multivariate logistic regression. It also compared well with the clinician's expertise, which raises the possibility of being useful as an automated alert tool. Because an ANN learns directly from previous data obtained in the institution where it is to be used, this makes it particularly amenable for application to evidence-based medicine. Given the variety of practices and equipment being used in different hospitals, this may be particularly relevant in the context of caring for preterm newborns who are on mechanical ventilation.