Acne vulgaris is the most common dermatological disorder worldwide, causing significant physical and psychological morbidity. Topical combination therapy has shown superior efficacy compared to monotherapy, especially when combined with retinoids. Few studies have directly compared combined formulations. This evaluator-blinded pilot study compared the efficacy and tolerability of two marketed topical combination acne gels, clindamycin 1%-tretinoin 0.025% (CT) and benzoyl peroxide 2.5%-adapalene 0.1% (BA) in 20 patients with mild to moderate acne vulgaris. Gels were applied daily on opposite sides of the face for 21 days. The primary outcome was difference in transepidermal water loss (TEWL) at the end of treatment. Secondary endpoints were skin moisture content measurement, Investigators' Global Assessment, subject self-assessments (SSA) of burning/stinging, itching, erythema, and dryness/scaling, and Comparative Participant Satisfaction Questionnaire (CPSQ). Efficacy was assessed by inflammatory and non- inflammatory acne efflorescences counts. TEWL increased significantly for both CT and BA (+57.74%, P=0.002; +58.77%, P<0.001); skin moisture content significantly decreased only for BA (-16.47%, P=0.02). Only BA showed a significant increase in erythema and dryness/scaling (P=0.027 and P=0.014) and in SSA burning/stinging (P=0.04). Patient satisfaction evaluation also reflected the strong BA irritation. Although CT and BA both reduced acne lesions (P<0.001) and more patients preferred to continue with CT, subject perception of acne improvement was higher for BA. These findings suggest that CT and BA have similar efficacy in the treatment of mild to moderate papulopustular acne. However, CT was better tolerated than BA by both medical and subject evaluation. CT is an effective and tolerated treatment option.J Drugs Dermatol. 2021;20(3):295-301. doi:10.36849/JDD.2021.5641.