Background: Acne vulgaris is the most common cause for dermatology visits and is one of the most common diseases that people experience during their lives. Although this disease is not life-threatening, it may affect the life quality of the patients because of developing irreparable complications on the skin. Dermatologists are in agreement about topical treatment in the mild to moderate acne vulgaris, but extensive using of tropical antibiotics and drug resistance have decreased their therapeutic benefits. In this study, we tried to compare the therapeutic effects of tropical azithromycin and clindamycin. Methods: This study was designed and performed as a double blind, randomized clinical trial. Thirty two patients with mild to moderate acne were treated with azithromycin and 30 patients, who were matched with the former group based on age, sex and severity of the disease, were treated with clindamycin for 12 weeks and results of their treatment were compared with each other. Results: results of this study showed that ratio of response to treatment and decreasing the grade of the disease and number of nodules, papules and pustules were not significantly different in the first month of the treatment in both groups while just the number of nodules in the group on azithromycin showed more decrease in the last months of treatment in comparison with clindamycin (0.88±0.75 vs. 0.25±0.75, p=0.015). Also, clindamycin had more side effects, but the rate of satisfaction with both drugs were high and showed no difference. In this study, no significant association was found between sex and response to treatment and evaluation of association between age and response to treatment showed a significant reverse association between age and decreasing the number of pustules (p=0.002 , r= - 0.492). Conclusion: sum of findings in this study show that topical azithromycin is an effective antibiotic with acceptable side effects and high degree of satisfaction in patients and it can be used for the treatment of mild forms of acne.