Background: Acne vulgaris is a common skin disease that affects 85% to 100% of people at some time during their lives. It is characterized by noninflammatory follicular papules or comedones and by inflammatory papules, pustules, and nodules in its more severe forms. Aims: To compare the efficacy of combination treatment of clindamycin+salicylic acid, versus clindamycin+tretinoin versus clindamycin alone in the treatment of the mild-to-moderate acne vulgaris. Methods: This was a single-blinded, randomized clinical trial.Forty-two female patients (age range: 15-25 years) with mild-to-moderate acne vulgaris were selected randomly and subsequently randomized to 3 groups. Group A patients were treated with 1% clindamycin lotion (C lotion) twice daily. Group B patients were treated with 1% clindamycin+0.025% tretinoin lotion once nightly (CT lotion). Group C patients were treated with 1% clindamycin+2% salicylic acid lotion twice daily (CS lotion) for 12 weeks. For comparison of efficacy of these treatments, and regarding the skewed distribution of the data, Kruskal-Wallis Test and Mann-Whitney U test were used. SPSS software was used for statistical analysis. Results: There was a significant difference between 3 types of treatment in the respect of the total lesion count (TLC) improvement ( P = 0.039). The efficacy of treatment on Acne Severity Index (ASI) was maximum for CS lotion (81.80% reduction in ASI). CT lotion reduced ASI by as much as 73.73% during 12 weeks of treatment. The efficacy of C lotion was calculated to be 37.87% in the reduction of ASI. Conclusions: Our data suggested that the efficacy of CS lotion was significantly more than C lotion with respect to the TLC and ASI, although there was no significant difference between CS and CT lotion