Acne vulgaris is a very common skin disorder and topical combination therapy in acne produces greater and faster results, minimizes adverse effects and improves compliance. The objective of this study was to compare the efficacy and safety of combination of topical 1% clindamycin and 0.1% adapalene with combination of topical 1% clindamycin and 2.5% benzoyl peroxide in mild to moderate acne vulgaris. Our study was done on 120 patients diagnosed with mild to moderate acne on face (as per Indian Acne Alliance grading for severity of acne). They were randomly assigned into 2 groups (A and B) of 60 each, group A having received combination of topical 1% clindamycin and 0.1% adapalene while group B having received combination of topical 1% clindamycin and 2.5% benzoyl peroxide once daily at night for 12 weeks. Efficacy assessment was done by comparing acne lesion counts at follow ups with their baseline lesion counts [total, noninflammatory and inflammatory acne lesion counts ] and safety assessment was done to determine the comparative local and systemic tolerability at the end of 4, 8 and 12 weeks. Significantly greater reduction in mean percentage of total (-0.70±0.05 vs -0.51±0.03), noninflammatory (- 0.68±0.07 vs -0.49±0.03 ) and inflammatory (-0.77±0.06 vs -0.57±0.06) acne lesion counts was seen in group A than group B at 12 weeks, ( P < 0.001 - for all types of acne lesion counts ). Group A was better tolerated than group B with less irritation (52.5%vs 72.4%, P < 0.027). Thus, we conclude that the combination of topical 1% clindamycin and 0.1% adapalene is superior to combination of topical 1% clindamycin and 2.5% benzoyl peroxide in the treatment of mild to moderate acne vulgaris.