Background: Spironolactone is an effective treatment for female patients with acne vulgaris. However, topical spironolactone could be a valuable treatment option in both male and female acne patients due to the less possibility of systemic side effects with its topical formulation.Objective: To evaluate the efficacy and safety of 5% spironolactone cream in the treatment of mild to moderate acne vulgaris.Methods: In this pilot clinical trial, topical spironolactone 5% was evaluated to treat patients with mild to moderate acne twice a day for 8 weeks. The rate of improvement as any alterations in the number of open and closed comedones, facial inflammatory papules, and acne global grading scores were assessed. Moreover, skin biometric characteristics including skin hydration, erythema, transepidermal water loss (TEWL), pH, sebum, and Propionibacterium acnes bacteria activity were also assessed following the treatment.Results: Fifteen patients participated in our study with a mean age of 25 ± 4.87 years old. A total of 66.6% (n = 10) were female and 33.4% (n = 5) were male. The number of acne papules, open and closed comedones, and acne global grading score decreased significantly 4 and 8 weeks after the beginning of treatment (P < .05). No considerable side effect was reported. Moreover, there was no significant difference between the skin hydration, melanin, erythema, TEWL, pH index, sebum, and P acnes bacteria activity before, 4, and 8 weeks after the treatment with topical spironolactone cream (P > .05). Conclusion:The topical 5% spironolactone cream seems to be an effective and safe treatment of acne vulgaris in both male and female patients.