Copyright © 2015 by The National Association of Neonatal Nurses. Background: Catheter-associated Candida bloodstream infections are a common and serious problem in the neonatal intensive care unit (NICU). Several prophylactic regimens have been developed including oral administration of nonabsorbable antifungals and intravenous infusions. No reports to date have employed a topical regimen. Purpose: To evaluate the effectiveness of topical nystatin cream in preventing catheter-associated Candida sepsis. Methods: A retrospective descriptive design was used to determine the incidence of Candida sepsis in extremely lowbirth weight (ELBW, < 1000 g at birth) infants who were treated with topical nystatin cream for Candida bloodstream infection prophylaxis between January 1, 2000, and December 31, 2010. The electronic medical records of study infants were reviewed to establish the incidence of Candida sepsis. Results: A total of 464 ELBW infants were admitted to the NICU during the study period. Three infants (0.65%) developed Candida sepsis. Implications for Practice: These data demonstrate that a topical nystatin cream protocol is associated with a very low rate of Candida sepsis in ELBW infants with central catheters. The use of this protocol may contribute to a decrease in the morbidity and mortality rate associated with catheter-associated Candida infections in ELBW infants. Implications for Research: Before generalizations can be made as to the safety and efficacy of this protocol as compared to enteral and parenteral prophylactic treatments and in other institutions, large multicenter randomized controlled trials are required.