Acne vulgaris is a distressing skin condition which can carry with it significant psychological disability. Patients with acne are more likely to experience anger and are at increased risk of depression, anxiety, suicidal ideation. It is one of the most common conditions for which patients seek dermatological care and is a common disorder of the skin that affects individuals of all races and ethnicities. Acne is a chronic and multifactorial skin condition affecting about 80% of persons aged 11 to 30 years, the majority of whom are adolescents. There has been an increasing focus on the extent to which oxidative stress is involved in the pathophysiology of acne. The aim of this study is to investigate the effect of Silymarin, N-acetylcysteine and Selenium in the treatment of inflammatory acne. Methods: This study was carried out on 56 papulo-pustular acne patients of both sexes with age range of 14-30 years who were attend the outpatient clinic in Al-Hussain Teaching Hospital, Kerbalaa, Iraq; over a period of 6 months; from December 2011 till May 2012. Patients were allocated into four groups, 14 for each, treated as follow: Silymarin, N-acetylcysteine , Selenium and placebo. In addition to 28, age and sex- matched healthy subjects who serve as control group for baseline comparison. To all patients, serum malondialdehyde (MDA) , Glutathione (GSH) and Interleukine -8 (IL-8) were estimated at baseline and at the end of treatment after 8 weeks, In addition to that, the clinical follow up was done every two weeks in order to assess the changes in the number of inflammatory lesions. Results: Administration of antioxidants ; Silymarin, N-acetylcysteine and Selenium to patients with acne vulgaris significantly reduce serum MDA level; and increased serum level of GSH after 8 weeks compared to pre-treatment value, also significantly reduce Interleukine -8 (IL-8) serum levels in patients with acne compared to pre-treatment value; and reduced the inflammatory lesions number by 53%, 50% and 37% after eight weeks respectively, compared to placebo. Conclusion: The results obtained in this study clearly showed the beneficial effect of using Silymarin, N-acetylcysteine and Selenium to patients with acne vulgaris as indicated by the clinical improvement that strongly and positively correlated with biochemical findings and confirmed the role of a new strategy in targeting the pathophysiological changes accompanied with acne by using antioxidant agents.