BACKGROUND: The oral transmucosal (OTM) route for administration of comfort medication in infants at the end-of-life has long been favored by our pediatric palliative care team but has rarely been described in the literature. OBJECTIVE: To determine the feasibility of implementing a standardized comfort care protocol using OTM medications in dying neonates. METHOD: A comfort protocol prescribing medication by the OTM route and standardized assessment were established. Each infant included in the study was assessed with the Neonatal Pain, Agitation, and Sedation Scale (N-PASS). Caretakers’ satisfaction was assessed using a questionnaire. The feasibility of implementing the protocol was determined by the proportion of assessments done when required, the rate of termination of the protocol, and the feedback from nurses using the protocol. RESULTS: Twelve patients were enrolled. Regular evaluations were performed 85% of the time. When the medication was given as needed, 71% of cases were evaluated before versus 63% when regular doses were given. The as-needed doses were followed by an assessment 30 minutes later in 49% of cases and in 41%, 60 minutes later, for a total of 64% in the hour after medication administration. The protocol was discontinued only for two patients who were discharged to continue end-of-life care at home. There were no significant adverse events reported. Finally, 17 of 18 nurses said they would recommend this protocol to other institutions. CONCLUSION: In the context of neonatal palliative care, the implementation of a standardized protocol for administration of drugs by the OTM route is feasible and safe. However, in the context of this study, adherence was limited because of too-frequent evaluations and misunderstanding of the protocol.