OBJECTIVE: Dydrogesterone (DG), a synthetic isomer of progesterone, plays a potential regulatory role in the periodontal environment. The aim of this study was to investigate the potential effects of DG on periodontitis under periodontal therapy (PT) and the underlying mechanisms related to oral microbiota. METHODS: As a cohort study, perimenopausal women with periodontitis and abnormal uterine bleeding associated with ovulatory dysfunction were screened. A total of 30 women received PT (PT group) and 30 women received PT and oral DG 10 mg twice/day for 10 days/month (PT + DG group). At baseline and 3 months after treatment, pocket probing depth (PPD), bleeding index (BI), bleeding on probing (BOP), plaque index, CRP, IL-6, and TNF-α were measured. Additionally, 16S rDNA sequencing was performed to determine the characteristics of oral microbiota, mainly in terms of abundance, diversity, composition, and community structure. RESULTS: Three months after treatment, the levels of PPD, BI, and BOP, as well as the levels of CRP, IL-6, and TNF-α in gingival crevicular fluid were significantly lower in the PT + DG group than those in the PT group. After treatment, a relatively lower microbial abundance, and some differences in microbial composition were revealed between the PT and PT + DG groups. At the genus level, significantly fewer Escherichia-Shigella, Porphyromonas, and Absconditabacteriales (SR1), and more Lactobacillus, Gordonia, Bifidobacterium, and Oribacterium were found in the PT group than in the PT + DG group. CONCLUSIONS: DG enhances the effect of PT on inhibiting inflammatory response in women with periodontitis by mediating oral microbiota.