OBJECTIVES: Assessment and management of symptoms exhibited by infants can be challenging, especially at the end-of-life, because of immature physiology, non-verbal status, and limited symptoms assessment tools for staff nurses to utilize. This study explored how nurses observed and managed infant symptoms at the end-of-life in a neonatal intensive care unit. METHODOLOGY/DESIGNMETHODS: This was a qualitative, exploratory study utilizing semi-structured face-to-face interviews, which were tape-recorded, transcribed verbatim, and then analyzed using the Framework Approach. SETTING: The sample included 14 staff nurses who cared for 20 infants who died at a large children’s hospital in the Midwestern United States. MAIN OUTCOME MEASURES: Nurses had difficulty recalling and identifying infant symptoms. Barriers to symptom identification were discovered based on the nursing tasks associated with the level of care provided. RESULTS: Three core concepts emerged from analyses of the transcripts: Uncertainty, Discomfort, and Chaos. Nurses struggled with difficulties related to infant prognosis, time of transition to end-of-life care, symptom recognition and treatment, lack of knowledge related to various cultural and religious customs, and limited formal end-of-life education. CONCLUSION: Continued research is needed to improve symptom assessment of infants and increase nurse comfort with the provision of end-of-life care in the neonatal intensive care unit.