Objective: The objective of this study was to evaluate the efficacy of targeted intermittent fluconazole prophylaxis (FP) to high-risk preterm (PT) infants. Study Design: Observational pre-post cohort study (n=524). Targeted FP (3 mg kg -1) was administered to PT infants (birth weights <1500 g and <6 weeks of age) who received broad-spectrum antibiotics for more than 2 days and had at least one additional risk factor for invasive candidiasis during the antibiotic administration period.Result: Invasive candidiasis decreased significantly from 15.3 to 6.2% during the FP period. Duration of parenteral nutrition (15.5 vs 19.2 days), central line (12.7 vs 15.8 days) and necrotizing enterocolitis rates (7 vs 9.5%) were significantly higher in the FP period. FP was administered to 89 (31.3%) infants; the median (range) number of doses was four (1 to 24) and duration was 7 (1 to 38) days. Conclusion: In the current study, targeted intermittent FP to a selected population of PT infants was efficacious in reducing the rate of invasive candidiasis, compared with historical controls.