In this study, an attempt has been made to differentiate Drug Resistant Tuberculosis (DR-TB) in chest X-rays using projection profiling and mediastinal features. DR-TB is a condition which is non-responsive to at least one of anti-TB drugs. Mediastinum variations can be considered as significant image biomarkers for detection of DR-TB. Images are obtained from a public database and are contrast enhanced using coherence filtering. Projection profiling is used to obtain the feature lines from which the mediastinal and thoracic indices are computed. Classification of Drug Sensitive (DS-TB) and DR-TB is performed using three classifiers. Results show that the mediastinal features are found to be statistically significant. Support vector machine with quadratic kernel is able to provide better classification performance values of greater than 93%. Hence, the automated analysis of mediastinum could be clinically significant in differentiation of DR-TB.