The aim of the study was to investigate the efficacy, safety and compliance of 500 mg azithromycin thrice weekly for 12 weeks in moderate inflammatory acne vulgaris. An open-label, noncomparative study was carried out for 12 weeks at Department of Dermatology and Plastic Surgery, La Sapienza University in Rome. Fifty-seven patients (20 male and 37 female) between 13 and 41 years of age, affected by moderate papulopustular and nodular acne vulgaris, were enrolled in the study. Azithromycin 500 mg was administered orally thrice weekly for 12 weeks. Patients were examined at baseline, 4 weeks, 8 weeks and 12 weeks (completion of treatment), evaluating both clinical (Global Acne Grading System, GAGS) and quality of life (Acne Quality of Life Questionnaire, AQoL) improvements. Forty-six patients completed the study and showed significant improvement. Six patients interrupted their treatment, while five patients did not complete the study for unknown reasons. Side effects (diarrhea and abdominal pain) were recorded in eight patients. Azithromycin, 500 mg thrice weekly for 12 weeks, is a safe and effective treatment for moderate acne vulgaris with excellent patient compliance.