Comorbidities are a significant factor affecting the prognosis of patients with rifampicin-resistant tuberculosis (RR-TB). We evaluated the prevalence of comorbidities and their prognostic effects in a Chinese RR-TB cohort. In this study, we reviewed the clinical data of RR-TB patients who started anti-tuberculosis treatment in China between May 2018 and April 2020 by conducting a multicenter cohort study. A log-binomial regression model was used to analyze the relationship between comorbidities and the treatment outcomes of RR-TB. The burden of comorbidities among RR-TB patients in China was heavy, with 49.45% (670/1355) experiencing at least one comorbidity. The most common comorbidities were diabetes (17.79%), followed by other respiratory diseases (11.14%), other liver and kidney diseases (5.31%), hypertension (5.24%), immunodeficiency (4.94%), viral hepatitis or carriers (3.91%), severe heart disease (2.58%), tumours (1.11%), and chronic kidney disease or renal insufficiency (0.74%). Diabetes (RR = 1.31), severe heart disease (RR = 1.70), tumours (RR = 1.89), hypertension (RR = 1.28), aged ≥ 60 years (RR = 1.64) and 45-59 years (RR = 1.38), ethnic minorities (RR = 1.58), retreatment cases (RR = 1.34), and those not using the bedaquiline regimen (RR = 1.92) significantly increased the risk of unfavorable treatment outcomes. While higher education or above (RR = 0.49), employment (RR = 0.51), and having a normal (R = 0.53) or overweight (R = 0.56) BMI could reduce the risk of unfavorable treatment outcomes. Patients with RR-TB beared a substantial comorbidity burden in China. Notably, the presence of comorbidities such as diabetes, severe cardiac disorders, tumours, and hypertension markedly elevate the risk of adverse treatment outcomes in these patients. It is necessary to strengthen the screening and management of comorbidities to optimize the treatment strategies.© 2025. The Author(s).