A single-center randomized, placebo-controlled trial has found that intravenous fluconazole prophylaxis in preterm infants < or = 1,000 g with a central venous catheter or endotracheal tube until such infants no longer required intravenous access or attained 6 weeks postnatal age was effective in preventing fungal sepsis. Infants at high risk for fungal sepsis are preterm infants < or = 32 weeks' gestation with one or more of the following additional risk factors: receipt of more than 2 antibiotics, third-generation cephalosporins, histamine-2 receptor antagonists, postnatal steroids, parenteral nutrition, or intravenous lipids; central venous catheter, skin disruption, dermatitis, necrotizing enterocolitis, or abdominal surgery. Further study in larger populations is needed to explore whether antifungal chemoprophylaxis or other strategies may be effective in preventing fungal infection in high-risk neonates. Effective prophylaxis strategies will decrease the high mortality and morbidity associated with fungal infection in high risk infants.