Gastroesophageal reflux disease (GERD) is one of the most common problems in neonates. The main goals of infantile GERD treatment are maintaining clinical recovery, sufficient growth, and preventing the recurrence rate and related problems. Acid-suppressive therapy including H2RAs and PPIs are the basic pharmacologic therapy for adult and pediatric GERD. PPIs are more effective than H2RAs in GERD treatment. Neonatal GERD remains a difficult entity to define and manage, and additional studies to aid in the clinical diagnosis and management are needed. Neonatal GERD refractory to conservative and monotherapy is a dilemma and performing trials to evaluate the effect of a PPI or a H2RA plus prokinetics in the management of these neonates is necessary to prevent considering invasive diagnostic procedures and early surgical treatment. we performed three different clinical trials to survey the efficacy and safety of combined therapy including an H2RA plus a prokinetic or a PPI plus a prokinetic in neonatal GERD refractory to conservative and monotherapy.