Objective: Hypotonic fluids have been traditionally used in newborns. National Institute for Health and Clinical Excellence-2015 (NICE) fluid therapy guideline recommends the use of isotonic fluids as maintenance fluid therapy in term newborns. However, there is no clear evidence supporting this recommendation. This study aims to compare isotonic (5% dextrose in 0.9% sodium chloride (NaCl)) and hypotonic (5% dextrose in 0.45% NaCl) parenteral fluid therapies in hospitalized term newborns with regard to changes in plasma Na (pNa) and complications related with fluid therapy. Methods: This was a retrospective cohort study performed in a tertiary university hospital NICU between January 2016 and April 2018. Term newborns who were initially isonatremic or mildly dysnatremic (pNa 155 meq/L) and receiving fluid therapy for maintenance or replacement therapy after 48th postnatal hours were eligible for the study. Infants having specific diagnoses requiring extraordinary fluids were excluded. The primary outcome evaluated was the change in mean plasma Na (Delta pNa meq/L/h) at 24 h or at the end of intravenous (i.v.) fluid therapy. Secondary outcomes evaluated were the risk of hyponatremia, hypernatremia, and adverse events attributable to fluid administration. Results: Among the 108 included newborns, 57 received hypotonic fluid (5% dextrose solution in 0.45% NaCl) and the remaining received isotonic fluid (5% dextrose solution in 0.9% NaCl) therapy. The hypotonic fluid group showed a greater Delta pNa compared to the isotonic group (0.48 +/- 0.28 vs. 0.27 +/- 0.21 meq/L/h, p = .001). The risk of experiencing unsafe plasma Na decrease in the hypotonic fluid group (Delta pNa >0.5 meq/L/h) was higher than the isotonic fluid group (odd ratio: 8.46; 95% confidence interval (CI): 2.3-30.06). Six mildly hypernatremic babies between 48 and 72 h of postnatal age showed insufficient Na reduction despite the appropriate amount of fluid. No significant difference was found between the two groups in terms of other outcomes. Conclusion: The results of this study suggested that as maintenance or replacement fluid therapy in the newborn, hypotonic fluids, even 5% dextrose in 0.45% NaCl, can lead to unsafe plasma Na decreases in term newborns, while isotonic fluids are safe when started after the first few days of life. Although the results parallel NICE guidelines, before making recommendations regarding the removal of hypotonic fluids entirely from clinical practice in term newborns following the renal adaptation period; larger randomized controlled studies involving a wide range of babies are needed.