Background Respiratory distress syndrome (RDS) of prematurity is a major cause of morbidity and mortality in preterm infants, caused by deficiency of pulmonary surfactant and structural immaturity of the lungs. Preterms with RDS should be given a natural surfactant as early as possible. Early surfactant therapy (within 2 h of birth) should be considered for preterms with gestation periods less than or equal to 31 weeks if the need for intubation in the delivery room arises. Lack and unavailability of surfactant in middle-income and low-income countries can occur, and preterms with RDS are treated with ventilation only. Aim The aim of this study was to study the effectiveness of surfactant application in preterms less than 36 weeks with RDS. Short-term effectiveness was monitored by improvement of chest radiograph, oxygen saturation (SpO2), and blood gases with decreasing ventilatory settings after 6 h. Long-term effectiveness was monitored by fate, duration of oxygen therapy, and duration of hospital stay. Moreover, the adverse effects of surfactant were detected. Patients and methods This cross-sectional study was carried out over a period of 18 months in the neonatal ICUs of the Department of Pediatrics, Cairo University hospitals, and included 180 preterms less than 36 weeks of gestational age. We compared 90 preterms less than 36weekswithRDSwhoreceivedmorethanorequal toonedoseofsurfactanttherapy, with 90 controls who had RDS and were eligible for the criteria of administration of surfactant but could not receive surfactant because of its unavailability in the unit at their time of admission. The two groups were compared regarding the period of ventilation, the improvement in ventilator settings and the capillary blood gases after surfactant application, hospital stay, and complications of prematurity. Results Surfactant application significantly improved the preterms, as seen in improvement of radiograph, capillary blood gases, and SpO2. Six hours after administration of surfactant in the case group, 59 (65.6%) cases showed an improvement in capillary blood gases, and after 6 h of ventilation in the control group, only 21 (23.3%) showed improvement in capillary blood gases, with a P value of 0.001. A total of 60 (66.7%) cases had an improved SpO2 after 4 h, but this was seen in only 17 (18.9%) controls, with a P value less than 0.001. Findings of RDS in chest radiograph showed improvement in 60 (66.7%) preterms in the cases group, whereas in the control group, 37 (41.1%) preterms were only improved. However, the mortality rates and the incidence of bronchopulmonary dysplasia were slightly higher in the group that received surfactant, with P values of 0.488 and 0.530, respectively. Conclusion Surfactant application showed significant improvement in preterms with RDS, as seen in improvement of radiograph, capillary blood gases, and SpO2. The mortality rate and the incidence of bronchopulmonary dysplasia were significantly higher in the surfactant group. Risk factors that significantly increased the mortality rates and the hospital stay in cases that received surfactant were very low body weight, gestational age less than 32 weeks, Downe's score more than 7, severe pulmonary hypertension, and late-onset sepsis. Sustainable efforts to provide all preterms with RDS in low-middle income countries with surfactant therapy should be encouraged. [ABSTRACT FROM AUTHOR]