To observe the clinical efficacy of herb-partitioned moxibustion (HM) and ginger-partitioned moxibustion (GM) in the treatment of chronic atrophic gastritis (CAG) and explore the effect of moxibustion on DNA methylation in peripheral blood of CAG-related precancerous lesions.Methods:Seventy CAG patients who were treated in the Acupuncture and Moxibustion Department of Yueyang Hospital of Integrated Traditional Chinese and Western Medicine affiliated to Shanghai University of Traditional Chinese Medicine from May 2018 to October 2020 were randomly divided into an HM group and a GM group，with 35 cases in each group.“Zhongwan” (CV 12)，“Qihai” (CV 6)，bilateral “Zusanli” (ST 36)，and bilateral “Neiguan” (PC 6) were selected for treatment in both groups.The clinical efficacies were evaluated by comparing the symptom scores of traditional Chinese medicine (TCM) and the gastric mucosal changes under gastroscopy before and after treatment.Whole blood samples from two patients in each group were collected before and after treatment.Genome-wide methylation sequencing and bioinformatics analysis were used to observe the changes of DNA methylation sites and methylation status in the peripheral blood.Results:1) The post-treatment TCM symptom scores were lower than pre-treatment ones in both groups (both P<0.01).The scores of gastric pain and loss of appetite were lower in the HM group and heartburn and nausea scores were lower in the GM group after treatment (both P<0.01).The total clinical effective rates were 87.88% and 78.79% in the HM group and the GM group，respectively (P>0.05).The histopathological changes in the gastric mucosa atrophy and intestinal metaplasia of the two groups as well as the degree of mucosal inflammation in the HM group were improved after treatment (P<0.05).The total effective rates of gastroscopy were 82.14% and 69.57% in the HM group and the GM group (P>0.05).2) In the CG sequencing environment，there were 176 and 652 differentially methylated genes in the HM group and the GM group，respectively，before and after treatment.In the HM group，the KEGG pathways of genes involved in the differentially methylated region (DMR)-anchored promoter region before and after treatment included cAMP，AMPK，and NF-κB signaling pathways，ubiquitin-mediated proteolysis，etc.，while in the GM group，the KEGG pathways included mTOR and HIF-1 signaling pathways，metabolic pathway，cell apoptosis，etc.Conclusion:Both HM and GM can improve the clinical symptoms of CAG patients and alleviate pathological conditions such as gastric mucosal atrophy and intestinal metaplasia.HM is advantageous in improving the symptoms of gastric pain and loss of appetite，while GM is potent in improving the symptoms of heartburn and nausea.Moxibustion can affect the DNA methylation levels in the DMR of the whole genome in the peripheral blood of CAG patients，which may be one of the epigenetic regulatory mechanisms of moxibustion against CAG.