Objective: To analyze the effects of caffeine in preventing ventilator-associated pneumonia (VAP) in premature infants to provide research basis for effective formulation of treatment plan. Methods: A total of 108 premature infants with neonatal respiratory distress syndrome (NRDS) from January of 2018 to December of 2019 were selected; they were divided into the study group and the control group by random number table method. 54 cases were included in each group. The infants in the two groups were treated with nasal intermittent positive pressure ventilation (NIPPV) after tracheal extubations. At the same time, the infants in the study group were treated with intravenous injection of caffeine citrate, while the infants in the control group were treated with intravenous injection of aminophylline. The incidence of VAP, the mechanical ventilation time, the hospitalization time and the incidences of other complications between the two groups were observed and compared. Blood gas indexes such as the arterial partial pressure of carbon dioxide (PaCO2) levels, the arterial partial pressure of oxygen (PaO₂) levels, and the pH values before the first extubation, 1 hour after extubation, 12 hours after extubation between the two groups were monitored. Results: There were 3 cases of VAP in the study group and 10 cases in the control group, and the infection rates were 5.56% and 18.52% respectively. The difference was statistically significant (P<0.05). The arterial blood pH value and PaCO2 levels of the infants in the two groups increased gradually after extubation, and the arterial blood PaCO2 levels decreased gradually after extubation. Twelve hours after extubation, the arterial blood pH value and PaO₂ level of the children in the study group were higher than those in the control group, and the arterial blood PaCO2 was lower than that in the control group. The differences were statistically significant (P<0.05); the total incidences of other complications, the ventilation time, and the hospitalization time of the children in the study group were lower than those in the control group (P<0.05). Conclusion: For the premature infants with NRDS, treatment of NIPPV combined with caffeine can shorten the duration of mechanical ventilation, reduce the incidence of VAP, improve the blood oxygenation level and reduce complications. The curative effects are better than those of aminophylline.