Despite guideline-based therapy, some patients with Mycobacterium avium complex pulmonary disease (MAC-PD) experience treatment failure. We analyzed the clinical courses of 271 patients with treatment-refractory MAC-PD who discontinued therapy after at least 12 months. Patients were categorized into two groups-the retreatment group, who resumed antibiotics due to clinical or radiological deterioration, and the stable group, who did not require antibiotics. Of the study patients, 138 (51%) were in the retreatment group, whereas 133 (49%) were in the stable group. In the multivariate analysis models, an elevated erythrocyte sedimentation rate (adjusted hazard ratio [aHR] =1.01), the presence of a cavity (aHR = 1.75), and the number of lobes affected by bronchiectasis (aHR = 1.21) were associated with the need for retreatment. Our data indicated that approximately 50% of the patients with refractory MAC-PD who discontinued antibiotics eventually required retreatment, which was influenced by the extent of lung destruction or inflammation. These findings can aid in determining treatment strategies for patients with refractory diseases.