AIM: To examine the immune responses in patients diagnosed as grade C periodontitis during orthodontic treatment. MATERIALS AND METHODS: Our study included seven orthodontic patients with grade C periodontitis and measured their levels of inflammatory cytokines in gingival crevicular fluid and plasma before orthodontic treatment, during the alignment and levelling phase, and during the detailing and finishing phase. The key signal pathways in the orthodontic process of patients with periodontitis were detected by KEGG analysis. RESULTS: Studies have shown that orthodontic treatment brings great improvement to patients with grade C periodontitis, and most of the local/systemic inflammatory cytokines can be reduced after orthodontic treatment. Simultaneously, orthodontic treatment can reduce the percentage of IFN-γ CONCLUSION: Orthodontic treatment can effectively control the local and system levels of inflammation in patients with grade C periodontitis, with IL-17A and TNF-α as potential distinctive inflammatory markers for orthodontic-periodontal combined treatment in individuals with periodontitis.