Purpose: Combination of benzoyl peroxide (BPO) with topical antibiotics can lead to higher efficacy and less bacterial resistance, but it in turn increases adverse effects such as skin irritability and dryness. In this study, the efficacy of combination therapy of niosomal BPO 1% and clindamycin (CL) 1% is compared with niosomal CL in acne vulgaris. Methods: This is a double-blind clinical trial study on 100 patients with acne vulgaris in Afzalipour hospital in Kerman. Patients were randomly divided into 2 groups (case and control). The case group received niosomal combination of BPO 1% and CL 1%.The control group received niosomal CL1%. The efficacy of treatment protocols was evaluated in 2nd, 4th, 8th and 12th weeks of treatment by counting lesions (severity and grading acne lesions) and quality of life (QoL). Furthermore, side effect were evaluated at each treatment visits. Results: The reduction in mean percentage of acne lesions in case group (treated with BPO 1% and CL1%) (64.21%) was higher than control group (treated with niosomal CL 1%) (59.04%), but the statistical difference was not significant. Sum of excellent and good results were found in 80% and 76.1% of case and control groups, respectively (P=0.377). Also adding BPO to the treatment formulation in case group did not increase adverse effects, as statistical difference between 2 groups was not significant. Conclusion: Combination of niosomal BPO 1% and CL 1% in treatment of acne vulgaris showed higher efficacy with no increase in adverse effects in comparison with niosomal CL 1%, but the statistical difference was not significant.