BACKGROUND Fluconazole has shown to be effective in reducing both colonization and invasive Candida infection (ICI) in ELBW neonates; we conducted a randomized trial to compare oral nystatin with intravenous fluconazole for prophylaxis against invasive Candidiasis in high risk neonates. METHODS By using SPSS, preterm less than 30 weeks gestation and/or birth weight 1200 grams or less assigned to receive either intravenous Fluconazole (6 mg/kg q72 hr for 1(st) week then q48 h for 6 wks) or oral Nystatin (100,000 unit q8 hr for 6 wks). The medications commenced at one week of age after obtaining the base line investigations and check for Candida colonization by urine culture and rectal swab; subsequently all lab work and the clinical data were monitered regularly. Risk factors were assessed. The data collected prospectively looking for primary end point the invasive Candida infection (ICI) and 2 ndry outcomes include medication safety, tolerance and cost. RESULTS 65 neonate randomly assigned however only 57 neonates comleted the study 33/57 (57%) to intravenous fluconazole group and 24/57 (42%) to oral nystatin group. No differences in birth weights Nystatin (1.15 Kg) Fluconazole (1.01 Kg), gender males (26/57), female (32/57), Gestational age (29.28 vs l28.22) or risk factors between the two groups. Rectal swab Colonization occurred in 2/24 (8%) in Nystatin group and 4/33 (12%) in the Fluconazole group, but none of the neonates developed ICI or side effects, although in the Fluconazole group transient transaminase elevation 2SD standard deviation above the mean was observed. Central line duration was 2 SD above the mean for fluconazole group, The cost of the Fluconazole treated group (7,581 SAR) 106.4 US/pt double the cost of Nystatin treated group (3,375 SAR) 50 US/pt. CONCLUSIONS Intravenous Fluconazole and oral Nystatin at the prophylactic doses are equally effective and safe in preventing (ICI) in preterm neonates, however oral Nystatin is readily available, easily administered with lower cost per neonate.