To investigate the risk factors of initial non-invasive ventilation(NIV) failure and its association with adverse outcomes in very low birth weight infants (VLBWI). A retrospective cohort study was conducted, collecting clinical data of 2 102 VLBWI who received NIV within 30 minutes after birth, admitted to 18 NICU of Suxinyun Neonatal Perinatal Collaboration Network (SNPN) from January 1, 2019 to December 31, 2022. According to the outcome of NIV within the first 72 hours, the study cohort was divided into success group and failure group. Univariate analysis and multivariate Logistic regression analysis were performed to identify risk factors for NIV failure and its association with adverse outcome. A total of 2 102 VLBWI were included, consisting of 1 078 males (51.3%). The gestational age was 29 (28, 31) weeks, and the birth weight was 1 250 (1 090, 1 380) g. The initial NIV failure rate was 15.3%(321/2 102). Multivariate Logistic regression analysis showed that smaller gestational age (=0.67, 95% 0.61-0.74, 0.001), maternal hypertensive disorders during pregnancy (=10.31, 95% 7.48-14.21, <0.001), Apgar score at the first minute ≤7 (=1.40, 95% 1.01-1.93, 0.042), grade 3-4 respiratory distress syndrome (RDS)(=2.85, 95% 1.69-4.81, <0.001), ≥2 times pulmonary surfactant (PS) treatment (=3.78, 95% 2.09-6.83, <0.001), fraction of inspired oxygen (FiO)>0.30 (=2.21, 95% 1.64-2.98, <0.001) were all independent risk factors for initial NIV failure. The failure group had higher risks of mortality (=10.19, 95% 6.50-15.97, 0.001), pneumothorax (4.33, 95% 1.59-11.79, =0.004), neonatal pulmonary hemorrhage (=8.48, 95% 4.08-17.64, <0.001), moderate to severe bronchopulmonary dysplasia (BPD)(=1.75, 95% 1.19-2.56, =0.004), and intraventricular hemorrhage (IVH) ≥grade Ⅲ (2.18, 95% 1.27-3.73, =0.004) compared to the success group. Small gestational age, maternal hyertensive disorders during pregnancy, Apgar score at the first minute ≤7, grade 3-4 RDS, PS treatment ≥2 times and FiO >0.30 are risk factors for initial NIV failure in VLBWI. Initial NIV failure is associated with increased risk of mortality, pneumothorax, pulmonary hemorrhage, moderate to severe BPD, and IVH ≥grade Ⅲ.