Antifungal prophylaxis has been proposed for liver transplant recipients at increased risk for invasive mold infection. Risk factors for invasive mold infection after liver transplantation were selected to divide recipients into 3 groups: (1) high risk-transplantation on hemodialysis or delay of hospital discharge beyond day 7 after transplantation because of allograft or renal insufficiency; (2) intermediate risk-retransplantation or transplantation for fulminant hepatic failure; (3) low risk-absence of conditions in groups 1 and 2. During an intervention period (February 1999-April 2001), prophylactic administration of a lipid complex of amphotericin (Abelcet) at 5 mg/kg intravenously every 24 to 48 hours was recommended for high-risk recipients. The frequency of mold infection was compared to that of a preintervention period (February 1998-January 1999) when antifungal prophylaxis was not provided. During the intervention period, invasive mold infection developed in 2 (6%) of 35 high-risk recipients, 0 of 28 intermediate-risk recipients, and 1 (0.5%) of 187 low-risk recipients. Overall, of 58 liver transplant recipients, 3 (5%) developed an invasive mold infection during the preintervention period, compared with 3 (1%) of 250 during the intervention period (P = 0.08). The only death from invasive mold infection occurred during the preintervention period. Rates of pulse corticosteroid treatment of rejection and cytomegalovirus infection were lower during the intervention period. In conclusion, readily identifiable patient characteristics can be used to stratify liver transplant recipients for risk of invasive mold infection. Antifungal prophylaxis given to high-risk recipients may provide cost-effective prevention of these infections.