Respiratory distress syndrome (RDS) is a common problem in premature babies who born before 37 weeks of gestation. It occurs due to lack of pulmonary surfactant, which is a phospho-lipoprotein produced by alveolar cells at the last stage of lung development (Lawn etal, 2014). There are many risk factors of RDS among premature neonates including; born before the 28th week of gestation and Low birth weight (Edwards etal, 2013). An estimated 2.9 million neonatal deaths occur each year worldwide, the majority of which happen in developing countries (Edwards etal, 2013). RDS can be fatal especially over the first 2 to 3 days if not treated with extra oxygen, surfactant replacement, and medicines (Zaman etal, 2013). Respiratory distress syndrome was first discovered in 1959 by Avery and Mead as a surfactant deficiency disease of the neonate (Avery & Mead, 1959) while in 1980, was the first administration of an exogenous surfactant as a treatment of RDS by Fujiwara and his colleagues (Fujiwara etal, 1980) According to the results of previous clinical trials and epidemiological studies on the effect of the exogenous surfactant therapy, it was significantly improve the survival of premature neonates with respiratory distress syndrome and decreased the incidence and severity of the disease (Fedakar & Aydogdu, 2011) and (Reuter etal, 2014). But it found that approximately 20% to 30% of neonates did not respond to surfactant administration disease (Swarnkar, 2015) and (Kommawar etal, 2017). The reasons for that are not clear till now. That’s why this study was conducted to assess the response of the premature neonates admitted in Benghazi pediatric hospital with respiratory distress syndrome (RDS) to the surfactant therapy and factors affecting it.