Background: Acne vulgaris is a common skin problem that is encountered in daily clinical work, affecting mostly the adolescent and young adult age group. Many topical therapies have been used in the treatment of mild to moderate types of acne vulgaris. However, none of these modalities is uniformly effective; furthermore, acne vulgaris is also associated with relapse and many topical side effects.Objective: To compare the effectiveness and side effects of topical 2% spironolactone solution and 1.5% clindamycin solution in the treatment of mild to moderate acne vulgaris.Material and methods: This was a single-blinded therapeutic clinical comparative study conducted at the Dermatology Center at Medical City in Baghdad, Iraq, from April 2019 to March 2020. Sixty-eight patients with mild to moderate acne vulgaris on the face were included. All sociodemographic data related to the disease were recorded for each patient. Patients were divided into two groups according to the type of therapy: group A (35 patients) used 2% spironolactone solution and group B (33 patients) used 1.5% clindamycin solution. All cases in both groups were instructed to use the solutions twice a day for 12 weeks in the same manner. Patients were seen every two weeks to evaluate the response to therapy and to report any topical side effects; then, follow-up was carried out for one month after cessation of therapy to evaluate relapse.Results: Spironolactone solution significantly decreased comedone count (p < 0.0001), while the clindamycin solution had no effect on comedones. Although spironolactone was slower than clindamycin solution in reaching the maximum therapeutic effect, the reduction in papules was comparable to that of clindamycin, but it exhibited a greater reduction of pustules (p > 0.05) and the Acne Severity Index (ASI; p > 0.05). Patients in the spironolactone group were more satisfied than those in the clindamycin group. Only minimal local side effects were reported in both groups that did not require cessation of therapy.Conclusion: Spironolactone solution is an effective and well-tolerated topical treatment for mild to moderate acne vulgaris and is superior to clindamycin solution.