Objective To compare the clinical efficacy and safety of isotretinoin erythromycin gel, a gel containing isotretinoin (0.05%) and erythromycin (2%), versus adapalene gel in the treatment of mild to moderate acne vulgaris. Methods A multicenter, randomized, open, parallel-controlled clinical study was conducted. A total of 192 patients with mild to moderate (Grade Ⅰ -Ⅲ ) acne vulgaris were enrolled in this study according to the grading criteria for acne severity in guidelines for the treatment of acne in China. Efficacy analysis was carried out in 169 patients and safety analysis in 190 patients. The patients were classified into trial group (n = 86) and control group (n = 83 ) to be treated with isotretinoin erythromycin gel or adapalene gel once a night for 6 weeks. Patients were evaluated at the baseline, on week 2, 4 and 6 during the treatment for the count of comedones (both open and closed), inflammatory papules and pustules, severity of acne and local or general adverse effects. Results After the start of treatment, the response rate gradually increased and severity of acne decreased in both groups. On week 6, the total response rate was 51.16% in the trial group and 40.96% in the control group (P ＞ 0.05), while a greater reduction in the count of pustules and inflammatory lesions was observed on week 4 and 6 in the trial group with a lower severity grade of acne compared with the control group (P ＜ 0.05 or 0.01 ). Adverse reactions were similar in both groups and manifested as tolerable local irritation. Conclusions The efficacy of isotretinoin erythromycin gel is similar to that of adapalene gel in the treatment of mild to moderate acne vulgaris, however, isotretinoin erythromycin gel seems superior to adapalene gel in reducing inflammatory lesions and rapidly improving severity of acne vulgaris.