Background: Cutibacterium (C. acnes) lipase activity can be reduced by topical antifungal cream called ketoconazole (KTZ). Additionally, it contains anti-inflammatory and anti-androgenic properties. The aim of this study was to evaluate the efficacy of topical ketoconazole 2% cream versus placebo in the treatment of mild and moderate acne vulgaris. Patients & Methods: 40 patients presented by mild and moderate acne were instructed to apply ketoconazole 2 % cream to the right half of the face and placebo to the left half of the face twice daily for 8 weeks Results: The mean percent reduction of inflammatory lesions (papules and pustules) and Total lesions count from baseline was significantly higher in ketoconazole than placebo. There was a statistically significant decrease in acne severity assessed by IGA score in both sides. The success rate of ketoconazole was significantly higher than placebo. In ketoconazole side, 17.5% of patients considered clear versus12.5%in control side and 52.5% almost clear versus 35% in control side. There was a statistically significant negative relationship between the therapeutic response and number of pustules in each side. Conclusion: Topical ketoconazole 2% can be an effective and safe treatment option for mild and moderate acne vulgaris.