Nausea and vomiting are one of the most important side effects of chemotherapy. Psychological factors such as anxiety, fear and negative moods have significant role in the chemotherapy induced emesis. Each chemotherapy course cause state anxiety like an invasive medical procedure. Therefore, we aimed to evaluate the effect of addition a sedative-anxiolytic agent to a 5-HT3 receptor antagonist in improving the control of chemotherapy induced emesis. Seventy chemotherapy courses in 18 children who received at least one highly emotogenic drugs were interpreted. Courses were randomly assigned to receive ondansetron (group I) or ondansetron plus hydroxyzine as a sedative agent (group II). Control of emesis was evaluated according to Soukop-Smith criteria. Performance of patients and degree of symptoms was assessed by using Lansky Play-Performance Scale and the Symptom Distress Scale, respectively. The complete and major control rate of acute emesis in group II (56%) was higher than group I (22%) (p= 0.006). The effect of combination antiemetic therapy was more obvious in female than male (p= 0.03), and in patients whose age greater than 10 years (p= 0.02). The mean play performance scale and symptom distress scale score were similar in two groups, before the chemotherapy course. After completion of course, play performance and symptom distress scale score were significantly better in group-II than that of group-I. Patients and parents in group-II declared significantly better sleeping quality, appetite, activity and mood than group-I. Hydroxyzine may enhance the activity of ondansetron in controlling acute chemotherapy-induced emesis and provided a better performance and lesser symptom distress.