Nosocomial infections are a major cause of morbidity and mortality among inpatients, especially infants in neonatal intensive care units. Reduction of nosocomial infections has become a major national patient safety initiative of the Centers for Disease Control and Prevention (CDC) and other organizations. The CDC has recommended, and many hospitals have adopted, use of waterless alcohol hand products in lieu of traditional handwashing to decrease nosocomial infections; there are few data, however, supporting this recommendation. In this large crossover study in 2 neonatal intensive care units, traditional antiseptic handwash was compared with an alcohol hand sanitizer. There was no difference in the risk of infections among the neonates in nurseries using these 2 products, but the alcohol regimen was associated with better skin health and improved quality of hand hygiene among nursing staff.