Objective To analyze the clinical efffcacy of fractional radiofrequency combined with retinoid drugs in the treatment of patients with moderate to severe acne and its inffuence on serum inffammatory factor levels. Methods A total of 80 patients with moderate to severe acne admitted to Yidu People’s Hospital from January 2022 to January 2024 were selected, and they were divided into group A and group B by the random number table method, with 40 patients in each group. Group A was treated with retinoid drugs alone, and group B was treated with fractional radiofrequency combined with retinoid drugs. The clinical efffcacy, lesion counts and inffammatory factor levels were compared between the two groups. Results The total effective rate of group B (95.00%) was higher than that of group A (77.50%) (P<0.05). After treatment, the counts of inffammatory and non-inffammatory lesions in group B were lower than those in group A (P<0.05). After treatment, the levels of IL-6, IL-17, TNF-α and CRP in group B were lower than those in group A (P<0.05). Conclusion Fractional radiofrequency combined with retinoid drugs can improve the clinical efffcacy for moderate to severe acne, effectively inhibit inffammatory severity and ameliorate skin lesions.