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BACKGROUND Respiratory distress syndrome (RDS) is defined as acute respiratory distress caused by surfactant deficiency-induced gas exchange disturbance in premature infants. We aimed to assess the effects of T-piece resuscitator combined with intubation-surfactant-extubation (INSURE) on short-term respiratory outcomes and complications in premature infants with RDS. MATERIAL AND METHODS This retrospective observational study included 100 premature infants with RDS who were treated between January 2019 and December 2023. The primary outcomes were blood gas and oxygenation indicators, including oxygenation index, partial pressure of carbon dioxide (PaCO₂), partial pressure of oxygen (PaO₂), and inhaled oxygen concentration. The infants were categorized into an INSURE group (n=50) and a combination group (n=50) based on treatment approaches. RESULTS Compared with the INSURE group, the combination group showed significantly lower oxygenation index, PaCO₂, and inhaled oxygen concentration, as well as significantly higher PaO₂ after intervention (P<0.05). In addition, the combination group had significantly increased blood oxygen saturation and shortened duration of nasal continuous positive airway pressure (nCPAP) ventilation compared with the INSURE group (P<0.05). Furthermore, the combination group exhibited significantly shorter length of hospital stay, duration of oxygen therapy, and duration of noninvasive ventilation, together with a lower incidence of complications (12% vs 30%, P<0.05). CONCLUSIONS T-piece resuscitator combined with INSURE technology may be associated with improved short-term blood gas and respiratory outcomes in premature infants with RDS, while potentially reducing the duration of respiratory support and incidence of complications. Nevertheless, further large-scale prospective studies are required to validate these findings.