Background: Acne vulgaris is a multi-factorial disease affecting many aspects of life. This study was conducted to compare the efficacy of fenugreek seed extract and oral azithromycin in the treatment of acne vulgaris. Methods: A total of 20 patients with acne vulgaris aged between 12 and 30 years old were entered into this 60-day, randomized, placebo-controlled, triple-blind study. The patients were randomly divided into two groups, (permuted block randomization, block size of 4), namely fenugreek and azithromycin groups. All the participants daily received two capsules containing 500 mg hydroalcoholic extract of fenugreek seeds or 125mg azithromycin, for two months. The patients were evaluated after 30 and 60 days from the start of the trial. The participants, investigators (the dermatologists who evaluated clinical responses), and statisticians who analyzed the data were blind for identity and allocation of the treatments. Results: The baseline GAGS scores in azithromycin and fenugreek groups were respectively equal to 19.66 and 23.12, and there was a reduction in both azithromycin (GAGS2=14.33) (P-value=0.019) and fenugreek extract group (GAGS2=22.75) (P-value=0.780) during the experiment. There was a statistically significant difference among the two groups (F= (2, 24) = 3.861, P=0.035). Conclusion: The effect of azithromycin was higher than fenugreek in the treatment of acne vulgaris.