Background: Preterm neonates are at a high risk of respiratory depression at birth. Incidence of respiratory distress is reported in 60-80% of the neonates born with the gestational age of less than 28 weeks and 15-30% of the neonates with the gestational age of less than 32-34 weeks. The present study aimed to compare the incidence and risk of failed extubation in using caffeine and aminophylline in the preterm neonates with the gestational age of ≤30 weeks in the periextubation period.Methods: This single-centered, parallel, open-label, randomized controlled trial was conducted in a tertiary care referral hospital in India during June 2014-2016. Neonates with the gestational age of ≤30 weeks who were intubated for a minimum of 24 hours were enrolled in the study. Neonates with major anomalies, heart disease, and sepsis were excluded from the study. After the random allocation of the infants to treatment with the standard dose of caffeine citrate and aminophylline methylxanthine, intubation continued for seven consecutive days with or without non-invasive ventilatory support. As the primary objective, the incidence and risk of failed extubation were assessed. Secondary objective of the research was to compare the relative incidence of acute adverse effects, persistent apnea, and the associated morbidities.Results: Neonates treated by caffeine were at a higher risk of extubation failure (1.09 times) adjusted with birth weight (31.5% versus 21.4%; RR=1.09; 95% CI: 0.81-1.46; P=0.55), which was not statistically significant. In addition, risk of apnea within seven days and after seven days of methylxanthine therapy was 1.57 (95% CI: 0.95-2.61) and 1.10 (95% CI: 0.95-2.61) times higher in the neonates with caffeine treatment. Also, rate of tachycardia was high in the neonates treated by aminophylline, which was statistically significant (RR=0.27; 95% CI: 0.13-0.56; P<0.001). Duration of non-invasive ventilator support, length of admission in the neonatal intensive care unit, O2 requirement at discharge, death before hospital discharge, and the associated morbidities were similar between the groups.Conclusion: According to the results, the incidence and risk of extubation failure were clinically high in the caffeine-treated neonates. However, aminophylline administration could continue as a prophylactic agent in developing countries under medical supervision.