Berberis vulgaris L. (barberry) is a very well-known herb in traditional medicine. Apart from its anti-inflammatory and antibacterial properties, the antilipogenic effect of barberry on the sebaceous glands in animals may further suggest it could be employed as an anti-acne agent. This study examined the effect of oral aqueous extract of barberry on acne vulgaris. Adolescents aged 12-17 years with moderate to severe acne vulgaris were randomly given oral gelatin capsules containing either aqueous extract of dried barberry (600 mg daily for 4 weeks, n = 25) or placebo (n = 24). Counts of facial noninflamed, inflamed, and total acne lesions, as well as the Michaelson's acne severity score were documented at baseline and at weeks 2 and 4. Both groups were comparable in terms of the patients' characteristics and baseline variables. After 4 weeks, the mean number of noninflamed, inflamed, and total lesions as well as mean Michaelson's acne severity score declined significantly by 43.25 ± 10.88% (median: 42.11%), 44.53 ± 11.78% (median: 45.45%), 44.64 ± 8.46% (median: 46.15%), and 44.38 ± 8.25% (median: 44.07%), respectively, among the extract receivers (p <.001 for all the changes). Similar changes were not significant in the placebo group. No notable complication or side effect was reported in relation to barberry. In conclusion, oral aqueous extract of dried barberry is a safe, well-tolerated, and effective choice in teenagers with moderate to severe acne vulgaris.