The REDUCE MRSA Trial (Randomized Evaluation of Decolonization vs Universal Clearance to Eliminate Methicillin-Resistant Staphylococcus aureus), a large multicenter, randomized controlled trial in adult intensive care units (ICUs), found universal decolonization to be more effective than surveillance and isolation procedures with or without targeted decolonization for reducing rates of MRSA-positive clinical cultures. The Agency for Healthcare Research and Quality and the Centers for Disease Control and Prevention subsequently published protocols for implementing universal decolonization in ICUs based on the trial's methods. Caution should be exercised before widely adopting these procedures in neonatal intensive care units (NICUs), particularly strategies that involve bathing with chlorhexidine and mupirocin application due to the potential for adverse events in their unique patient population, especially preterm infants. Large multicenter trials in the NICUs are needed to evaluate the efficacy, short- and long-term safety, and cost effectiveness of these strategies prior to their widespread implementation.