Background: Acne vulgaris is the most common disorder of pilosebaceous unit. Systemic antibiotics are known to be effective in its treatment. We performed this investigation to compare the efficacy of azithromycin with doxycycline in the treatment of acne vulgaris. Method: A twelve-week study was performed on 69 patients with moderate facial acne to compare the efficacy of oral azithromycin with oral doxycycline. Sixty patients completed the study. Patients in the treatment arm one were scheduled to receive 500 mg azithromycin once daily three times a week, and patients in the treatment arm two were instructed to use 100 mg doxycycline daily. All patients administered topical tretinoin cream every other night. Clinical assessment was made at baseline and then every 4 weeks. Result: There were statistically significant improvements in comedones and inflammatory lesion counts in both groups. Neither drug was shown to be more effective than the other. Conclusion: This study indicated that azithromycin had similar efficacy to doxycycline in reducing acne lesions.