Drug-resistant tuberculosis (DR-TB) remains a major global health problem. Early treatment of TB is critical; in the absence of rapid- susceptibility testing, the empiric selection of drugs should be guided by clinical data. This study aimed to determine the clinical predictors of DR-TB. From September 2010 to August 2017, sociodemographic and clinical characteristics were collected from 144 patients with tuberculosis at the Hospital Civil de Guadalajara, Mexico. Isolates were subjected to drug-susceptibility testing. Clinical predictors of DR-TB were determined using univariate and multivariate analysis. Any drug, isoniazid, and rifampin resistance rates were 47.7, 23.0, and 11.6%, respectively. The visualization of cavities and nodules through either chest radiography or computed tomography were independent predictors of DR-TB. In conclusion, early detection of DR-TB in this population could be based on multiple cavities being observed using chest imaging. This study's results can be applied to future patients with TB in our community to optimize the DR-TB diagnostic process.