Background: Although systemic treatment with oral azithromycin was considered as first line of therapy for inflammatory papulopustular acne. Its beneficial effects on severe nodulocystic type was not well studied before Objectives: To evaluate the efficacy, safety and tolerability of azithromycin as monotherapy for treatment of severe nodulocystic acne. Patients and Methods: The study was a prospective clinical trial recruiting 49 patients with severe nodulocystic acne. Azithromycin 500mg was given orally thrice weekly for 12 weeks. Four weekly follow up were performed for 3 months to assess clinical response and report any adverse effects. Results: Compared to baseline, there was marked and significant reduction in the number of the inflammatory lesions at 12 weeks of treatment with the clearance of 87.05% of the papules, 90.5% of the pustules and 78.82% of the nodulocysts. At the end of the treatment there was a remarkable clearance of the inflammatory lesions in the majority of the patients ( 63% of the patients showed excellent response to the treatment, 19.5% good response, 8.6% moderate and only 8.4% reported poor response). Adverse effects were mild and mainly gastrointestinal. Conclusion: Azithromycin is an effective, safe and well tolerated alternative in treatment of severe nodulocystic acnewith minimal adverse effects