Background and Objectives: Nasal continuous positive airway pressure (NCPAP) is a useful method of respiratory support after extubation. However, some infants fail despite CPAP use and require reintubation. Some evidence suggests that synchronized nasal intermittent positive pressure ventilation (NIPPV) may decrease extubation failure in preterm infants. Nonsynchronized NIPPV (NS-NIPPV) is being widely used in preterm infants without conclusive evidence of its benefits and side effects. Our aim was to evaluate whether NS-NIPPV decreases extubation failure compared with NCPAP in ventilated very low birth weight infants (VLBWI) with respiratory distress syndrome (RDS). Methods: Randomized controlled trial of ventilated VLBWI being extubated for the first time. Before extubation, infants were randomized to receive NCPAP or NS-NIPPV. Primary outcome was the need for reintubation within 72 h. Results: 220 infants were included. The mean ± SD birth weight was 1,027 ± 256 g and gestational age 27.8 ± 1.9 weeks. Demographic and clinical characteristics were similar in both groups. Extubation failure was 32.4% for NCPAP versus 32.1% for NS-NIPPV, p = 0.98. The frequency of deaths, bronchopulmonary dysplasia, intraventricular hemorrhage, air leaks, necrotizing enterocolitis and duration of respiratory support did not differ between groups. Conclusions: In this population of VLBWI, NS-NIPPV did not decrease extubation failure after RDS compared with NCPAP.