Objective To analyze the drug resistance of rifampicin and isoniazid in patients with tuberculosis in Yantai City, Shandong Province, from 2013 to 2019.Methods Data related to pathogenetically positive tuberculosis patients were collected in the China Disease Control and Prevention Information System. Trends in drug resistance changes were analyzed using the chi-square trend test. The unifactorial and multifactorial analyses of drug resistance influencing factors were performed using the chi-square test and multifactorial logistic regression, respectively.Results Totally 4 977 patients with pathogenetically positive tuberculosis were enrolled in this study, and 226 (4.5%) were resistant to rifampicin and/or isoniazid, of which 37 (0.7%) were resistant to rifampicin only, 140 (2.8%) to isoniazid only, and 49 (1.0%) were multidrug resistant. There was an overall increasing trend in patient resistance rates with increasing years (χ2=9.111, P=0.003). The results of univariate analysis showed that there were differences in drug resistance rates in terms of patient origin, therapeutic classification, level of therapeutic management and whether or not there was comorbid diabetes mellitus (P<0.05). Logistic regression analysis showed that retreatment (OR=3.691, 95%CI: 2.737-4.978) and the combination with diabetes mellitus (OR=1.703, 95%CI: 1.055-2.748) were risk factors for tuberculosis drug resistance.Conclusion The rate of resistance to rifampicin and/or isoniazid was low among patients with pathogenetically positive tuberculosis in Yantai City from 2013 to 2019, the trend of change in resistance suggests that prevention and control should still be strengthened in the future, and the risk of resistance was higher in patients who were retreated and complicated with diabetes mellitus.