Objective To evaluate the efficacy of isotretinoin soft capsule combined with clarithromycin in the treatment of moderate and severe acne. Methods A total of 128 patients with moderate and severe acne admitted to the Department of Dermatology of Guangxi Guiping People's Hospital from August 2020 to May 2021 were selected as the research objects. They were divided into observation group and control group by random number table method, with 64 cases in each group. The control group was treated with clarithromycin, and the observation group was treated with isotretinoin soft capsule on the basis of the control group. The Global Acne Grading System (GAGS) score, clinical effica, sex hormone levels [progesterone (P), testosterone (T), estradiol (E2)], incidence of adverse reactions and recurrence rate were compared between the two groups. Results The GAGS score of the two groups after treatment was lower than that before treatment, and the observation group was lower than the control group, the differencewas statistically significant(P<0.05). The total effectiverate of the observation group was 93.75%, which was higher than 81.25% of the control group, and the difference wasstatistically significant P<0.05). After treatment, the levels of P and T in the two groups were lower than those before treatment, and the level of E2 was higher than that before treatment, meanwhile the levels of P and T in the observation group were lower than those in the control group, and the level of E2 was higher than that in the control group, the differene was statistically signifiant (P<0.05). There was no significan differnce in the incidence of adverse reactions between the two groups (P>0.05). After 6 months of treatment, the total recurrence rate of the observation group was 1.56%, which was lower than 9.38% of the control group, and the differencewas statistically significant(P<0.05). Conclusion Isotretinoin soft capsule combined with clarithromycin is effective in the treatment of moderate and severe acne, which can effectivelyimprove the clinical symptoms of patients with moderate and severe acne, regulate the level of sex hormones in vivo, reduce the risk of recurrence, and have less adverse reactions.