Acne vulgaris is a common skin disease seen primarily in adolescent and young adults. As the treatment involves long term therapy with antibiotics, an agent with a long half life can be very useful in increasing the compliance. To evaluate the role of a monthly dose of azithromycin and compare it with daily doxycycline, we conducted this randomized comparative study. Sixty patients with moderate to severe acne were randomly assigned to two treatment groups, A & B. Patients in group A received 100 mg doxycycline daily in addition to topical 0.05% tretinoin cream, whereas patients in group B were given 500 mg azithromycin once a day for four days per month along with 0.05% topical tretinoin for a total of 12 weeks. Of the 60 patients, 22 in group A and 28 in group B were evaluated. The monthly dose of azithromycin was found to be as effective as daily doxycycline on a pure protocol basis and statistically significantly better than doxycycline by intention to treat analysis.