Background: The infectiousness of DR-TB is mainly determined by the sputum tuberculosis bacilliary load of the patient. However, evidence on DR-TB sputum smear grading and its factors in the study setting is limited. This study was aimed to assess the sputum smear grading and associated factors among DR-TB patients in Amhara regional state, Ethiopia.Methods: This was an institution based cross-sectional study on 520 bacteriological confirmed pulmonary DR-TB patients from September 2010 to December 2017 in the Amhara region Ethiopia. Epidata 4.2.00 and SPSS 20 were used for data entry and management, respectively. Ordinary logistic regression was fitted. A cut of p-value less than 0.05 in the multivariable ordinary logistic regression was considered to declare statistically significant variables.Results: Of all 520 bacteriological confirmed pulmonary DR-TB patients; 34.42% had 3+, 15.77% had 2+, 18.27% had 1+, 15.19% had scanty, and 16.35% had negative sputum smear grading results. The odds of having higher sputum smear grades were significantly associated with the patient's educational status of secondary (Adjusted Odds Ratio (AOR)=0.43, 95% Confidence Interval (CI): 0.21, 0.89), body mass index of 16 to 18.49 kg/m2 (AOR=1.81, 95%CI: 1.16, 2.84), and TB treatment history of two and more times (AOR=1.78, 95%CI: 1.24, 2.55).Conclusions: More than a third of the bacteriological confirmed pulmonary DR-TB patients in the study setting was highly infectious with the highest bacillary load. The odds of having a high bacillary load were significantly associated with the patient's TB treatment history, nutritional, and educational status.