BACKGROUND: Invasive candidiasis is a leading cause of mortality and morbidity in neonatal intensive care units. Treatment recommendations are limited by a lack of comparative outcomes data. METHODS: We identified all infants ≤ 120 days of age with positive blood, urine, or cerebrospinal fluid cultures for Candida species who received amphotericin B deoxycholate, fluconazole, amphotericin B lipid products, or combination therapy admitted to one of 192 neonatal intensive care units in the United States between 1997 and 2003. Primary outcome measures included overall mortality and therapeutic failure (combined outcome of duration of infection >7 days, need for additional antifungal therapy, or death before discharge). We compared outcomes by antifungal therapy using logistic regression, controlling for gestational age, day of life at start of antifungal therapy, delay in therapy, and site of infection. RESULTS: Overall, 138 of 730 (19%) infants died. On multivariable logistic regression, we observed higher overall mortality for infants receiving amphotericin B lipid products compared with infants receiving amphotericin B deoxycholate (odds ratio 1.96 [95% confidence intervals: 1.16, 3.33]; P = 0.01) or fluconazole (odds ratio 2.39 [1.18, 4.83]; P = 0.02). CONCLUSIONS: Infants treated with amphotericin B lipid products had higher mortality than infants treated with either amphotericin B deoxycholate or fluconazole. This finding may be related to inadequate penetration of amphotericin B lipid products into the kidneys, inappropriate dosing in premature infants, or unknown differences in acuity of illness in infants treated with amphotericin B lipid products.