Although guidelines recommend amikacin (AMK) inhalation therapy for difficult-to-treat nontuberculous mycobacterial lung disease (NTM-LD), data are limited regarding the safety and clinical efficacy of this salvage therapy. We retrospectively evaluated the treatment outcomes of 77 patients with refractory NTM-LD caused by Mycobacterium abscessus complex (MABC) or M. avium complex (MAC) who initiated AMK inhalation therapy between February 2015 and June 2016. MABC was the most common etiology ( n = 48, 62%), followed by MAC ( n = 20, 26%) and mixed infections ( n = 9, 12%). Isolates with macrolide resistance and baseline AMK resistance were identified in 63 (82%) patients and 5 (6%) patients, respectively. At 12 months after AMK inhalation therapy, 49% of patients had symptomatic improvement, whereas 42% had radiological improvement. Conversion to a negative sputum culture occurred in 14 (18%) patients, and the culture conversion rate was higher in patients infected with macrolide-susceptible isolates (7/14, 50%) than in those infected with macrolide-resistant isolates (7/63, 11%) ( P = 0.003). Significant decreases in sputum semiquantitative culture positivity occurred after AMK inhalation therapy ( P 〈 0.001). On multivariate analysis, conversion to a negative sputum culture was associated with mixed infections ( P = 0.009), a forced expiratory volume in 1 s of greater than 60% ( P = 0.008), and the absence of macrolide resistance ( P = 0.003). Thirty-eight percent of patients experienced adverse effects, with ototoxicity ( n = 15) being the most common. AMK inhalation salvage therapy may improve the treatment responses in some patients with refractory NTM-LD. However, considering the common adverse effects, further evaluation of the optimal dosage and intervals for AMK inhalation therapy is needed.