<b><i>Introduction:</i></b> Acne vulgaris is a widespread skin disorder. The aim of this study was to assess the effectiveness of wet cupping in the treatment of moderate to severe facial acne vulgaris. <b><i>Methods:</i></b> Between August 2018 and January 2020, eligible patients with moderate to severe facial acne were recruited in this single-blind, intervention-sham-controlled clinical trial in Iran. The intervention group received wet cupping twice and likewise the control group received sham cupping. Also, both groups received 500 mg azithromycin 3 times/week for 12 weeks. Acne grades were assessed 6 weeks and 12 weeks after beginning of the treatment by the dermatologist uninformed of group allocation and participant self-assessment. Quality of life was assessed with valid questionnaire before and after the treatment. <b><i>Result:</i></b> Totally, 103 patients completed the trial. The patients in the intervention group had better improvement and grade of acne compared to the control group at the end of the trial. Patients showed a shorter time to removing facial lesions in the intervention group in contrast with the control group (<i>p</i> &#x3c; 0.001). Quality of life significantly increased in the intervention group compared with the control group (<i>p</i> = 0.004). <b><i>Conclusion:</i></b> Wet cupping plus antibiotic therapy seems to be more effective than antibiotic therapy per se in patients with facial acne vulgaris.