Vancomycin has been used for more than 50 years in neonatal intensive care units (NICUs) as the therapy of choice for late-onset sepsis, mainly because Coagulase negative Staphylococci (CoNS) are common and mostly resistant to oxacyllin despitelow virulence and unusual association with fulminant sepsis. CUs due to several factors including its high pharmacokinetic variability, difficulty in reaching therapeutic plasmatic drug concentrations and progressively increasing minimum inhibitory concentrations (MIC). The increase of CoNS with higher MICs as well as the rise of infections caused by resistant gram-negative bacilli and candida should move to reconsider Vancomycin as first line treatment. Infections in neonates have a different behavior than in other populations and we consoder of utmost importance to consider the use of oxacyllin as first line antimicrobial therapy for late-onset sepsis.