Background: Medical management of neonates is often predicated upon safe and reliable vascular access which may be related to physiological monitoring, medical treatment, supportive therapy and diagnostic or procedural purposes. For this, peripherally inserted central catheters (PICCs) are deemed safe to provide vascular access and infusion related therapy in the neonatal intensive care setting. Purpose: PICCs are associated with a reduced incidence of complications compared to short peripheral catheters. Despite a reduced complication rate, the impact for the patient has to be considered severe. Difficult PICC guidewire removal during the insertion procedure is known to cause catheter damage, resulting in leakage or breakage of the catheter itself. The aim of this study was to assess and compare the incidence of therapy failure related to the use of preflush fluids (normal saline (NSS) versus diluted lipid solution(DLS)) used before PICC guidewire removal. Method and Setting: This was a retrospective observational study and performed on the Neonatal Intensive Care Unit (NICU) of the Women’s Wellness and Research Centre, Hamad Medical Corporation, Qatar. The single site study included 507 neonates who required intravenous therapy. Results: The results show that the use of a diluted lipid preflush resulted in significantly less therapy failures, compared with the control group. This remains significant after adjusting for day of insertion, gestational age, birth weight and catheter type.Conclusion: DLS preflush demonstrated a benefit over the use of a NSS preflush to enhance PICC guidewire removal in patients admitted to the NICU. The risk for the development of maintenance-related complications leading to premature removal of the device, decreased significantly if the preflush DLS was used. During the study period no known complications related to the used lipid solution were identified. Implications for Practice and Research: This study is the first of its kind ever published in international literature and supports the enhancement of guidewire removal by using a diluted lipid preflush. When the requirement for vascular access is most pertinent, using a diluted lipid preflush is a safe and effective method to remove the guidewire in order to facilitate long-term vascular access amongst the neonatal population.