To evaluate the efficacy of different drug combinations in treating severe gastroesophageal reflux (GER), we studied 80 children with GER. The patients were randomly divided into four groups: group A was treated with domperidone plus magnesium hydroxide and aluminum hydroxide, group B with domperidone plus alginate, group C with domperidone alone, and group D received placebo. At the time of diagnosis and 8 weeks after treatment the patients were clinically evaluated and underwent 24-h continuous esophageal pH monitoring. After treatment a complete regression of symptoms was observed in 16 of 20 patients in group A, in 8 of 20 in group B (A versus B, p < 0.018), in 9 of 20 in group C (A versus C, p < 0.034), and in 7 of 20 in group D (A versus D, p < 0.001). Moreover, there was a statistically significant improvement in several pH-metric variables studied in all treatment groups; in addition, a comparison of the pH-metric data of the four groups after treatment indicated that reflux variables were significantly lower in group A than in the other groups. We conclude that the domperidone plus magnesium hydroxide and aluminum hydroxide combination was more effective than the other drugs we used in treating GER and in modifying the objective pH-metric variables in pediatric patients.