Introduction: Bronchiectasis is an abnormal and permanent dilation of the bronchi. Bronchiectasis may be a local, in which only the airways of a limited area of the lung parenchyma are involved. However, bronchiectasis may be diffused, in which the wider airways areas of the lung are affected. Given that no study has ever compared the effect of levofloxacin with routine therapies, this study was conducted to compare the prophylactic effect of short-term treatment with levofloxacin and azithromycin in patients hospitalized in Zahedan, Iran. Materials and methods: This was a clinical trial study. After entering the study, 90 patients were randomly divided into two equal groups. In one group, levofloxacin patients received 5 days a month, and in the other group, azithromycin patients received a dose of 250 mg per day throughout the study. Patients were followed for one year, during which they were evaluated for the number of hospitalizations and the number of exacerbation cases. It was also explained to the patients that due to the use of blinding techniques, the type of administrated drug and the group in which they are placed will not be informed and if they are not satisfied, they will not enter the study. Initial patient information such as age and sex were recorded for each individual. At the end of the study, the data were entered into SPSS statistical software version 19 and examined based on descriptive statistics and independent t-test. The significance level was considered 0.05. Findings: According to the findings, the average number of exacerbations of bronchiectasis symptoms per year in azithromycin group was 4.42±2.00 and in levofloxacin group, was 2.44±1.34 and the average number of hospitalization cases per year in azithromycin group was 0.75±1.40 and in the levofloxacin group was 0.88±0.60 (p <0.001). Conclusion: The results of the present study showed a significant difference between the number of exacerbations and hospitalizations per year in levofloxacin and azithromycin groups, and the levofloxacin group indicates favorable results in this case. However, it is essential to conduct further studies on the effect of azithromycin and levofloxacin on the rate of exacerbation and hospitalization in patients with bronchiectasis.