Background & Objectives: Vertigo is often recognized as a gruesome clinical symptom in the emergency ward. Physicians often encounter problems with this complication in both the diagnosis and treatment phase. Vertigo is one of the most common causes for patient attendance at the emergency ward. Drug therapy is the most appropriate treatment for acute peripheral vertigo. Promethazine is one of the medicines used to treat acute vertigo in the emergency ward. This study evaluated the effect and complications of muscular promethazine and ondansetron in the treatment of peripheral vertigo. Materials & Methods: This study was performed as a double-blind randomized clinical trial in teaching hospitals of Yazd. In so doing, 160 patients observing inclusion criteria were selected for the study and randomly assigned intopromethazine and ondansetron groups. Then, 25 mg of intramuscular promethazine was administered to the promethazine group and 4 mg of intramuscular ondansetron was administered to the ondansetron group. Next, the severity of complications and clinical symptoms and the severity of vertigo at the time before and after receiving the drug for up to 2 hours were assessed. Results: The results of the present study showed that there was no significant difference between the two groups in terms of age, sex, underlying diseases, duration of vertigo and clinical symptoms of patients (P<0.05). Matching of the groups was carried out correctly. The mean severity of vertigo in the promethazine group was 6.9, 5.8, 4.1, 2.8 and 2.4, respectively at 0, 30, 60, 90 and 120 min after treatment, while in the ondansetron group, the severity of vertigo was 6.6, 5.5, 3.8, 2.5 and 1.8, respectively at these times. Although the severity of vertigo was lower in the ondansetron group than in the promethazine group, except for 120 min after treatment, there was no significant difference between the two groups. The result of Greenhouse-Geisser test also showed that there was totally no significant difference between the two groups over time (P=0.39). Besides, all side-effects were higher in the promethazine group. Conclusion: The findings of the present study showed that due to the similar effect of ondansetron and promethazine and the numerous complications of promethazine, ondansetron can be used as an alternative to promethazine in the treatment of peripheral vertigo in the emergency ward