Background: Although acitretin has been widely used for the treatment of psoriasis, additional safer and more effective approaches, including traditional Chinese medicine, are needed. Objectives: To investigate the efficacy and safety of total glucosides of paeony (TGP) combined with acitretin in the treatment of moderate-to-severe plaque psoriasis. Materials & methods: A randomised, double-blind, placebo-controlled, multi-centre clinical study was conducted. In total, 108 patients with moderate-to-severe plaque psoriasis were randomly assigned to treatment with "TGP plus acitretin" (group A) or "placebo plus acitretin" (group B) for 12 weeks. Results: After 12 weeks of therapy, the percentage of patients achieving a 50% reduction in Psoriasis Area and Severity Index was 90% in group A and 70.5% in group B (p<0.05). The rate of serum alanine aminotransferase elevation was 6.25% in group A and 20.4% in group B (p<0.05). Conclusion: TGP is conducive to enhancing anti-psoriatic efficacy and reducing liver damage due to acitretin. TGP combined with acitretin is a safe and effective treatment approach for moderate-to-severe plaque psoriasis.