Background: Retinaldehyde is a key molecule in the metabolism of vitamin A by keratinocytes. In order to evaluate its range of topical activity in acne, its comedolytic effect was compared to that of retinoic acid in the same vehicle, in the rhino mouse model. Methods: The animals were treated on the back daily for 5 consecutive days per week for 3 weeks. At the end of this period, histological slides were analyzed in order to quantify the features of comedones and epidermal thickness. Results: Topical treatment with a retinaldehyde (0.05% w/w) and a retinoic acid formulation (0.025% w/w) induced comedolysis and increased the epidermal thickness with the same intensity. Conclusion: These data indicate that retinaldehyde exerts a significant comedolytic activity.