Antibiotic resistance significantly impacts the success of Helicobacter pylori eradication. This study aimed to evaluate the antibiotic resistance patterns among a Chinese Yi ethnic population.Gastric biopsy specimens were collected from Chinese Yi patients undergoing endoscopy at 2 hospitals for H. pylori isolation and pathological assessment. Antimicrobial susceptibility testing (AST) was performed for amoxicillin (AML), tetracycline (TET), clarithromycin (CLR), metronidazole (MTZ), levofloxacin (LEV), rifampicin (RIF), and furazolidone (FZD) using Etest or disk diffusion. Univariate and multivariate logistic analysis were used to identify factors associated with antimicrobial resistance.From 501 gastric specimens, 262 H. pylori strains were isolated (52.3% culture rate). Of the 262 H. pylori-positive patients (110 men and 152 women, mean age 40.7 years), endoscopic findings revealed that 129 (49.2%) had chronic atrophic gastritis, 40 (15.3%) had peptic ulcers, and 2 (0.8%) had gastric malignancy. Pathological analysis revealed a high prevalence of moderate-to-severe chronic gastric atrophy (75.6%), intestinal metaplasia (14.7%), and dysplasia (0.8%). The overall resistance rates were the following: AML (0.0%), TET (0.4%), CLR (22.9%), MTZ (86.3%), LEV (39.7%), RIF (52.7%), and FZD (0.0%). Multi-drug resistance was observed in 32.1% of the strains. Age (for CLR, MTZ, and LEV) and female gender (for MTZ) were independent factors associated with antimicrobial resistance.Chronic gastric atrophy is highly prevalent among Yi patients, emphasizing the need for endoscopic screening and prompt H. pylori eradication to prevent gastric cancer. Due to high resistance, CLR, MTZ, and LEV should not be used empirically. In contrast, TET, AML, and FZD show negligible resistance, treatment regimens based on these antibiotics are likely to be effective.© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.