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Rationale Lengthy multi-drug, toxic, and low efficacy regimens limit management of pulmonary nontuberculous mycobacterial (PNTM) disease. Objective This phase 2 study investigated efficacy and safety of liposomal amikacin for inhalation (LAI) in treatment-refractory PNTM (Mycobacterium avium complex [MAC] or Mycobacterium abscessus) disease. Methods During the double-blind phase, patients were randomly assigned to LAI (590 mg) or placebo once daily added to their multi-drug regimen for 84 days. Both groups could receive open-label LAI for 84 additional days. Primary endpoint was change from baseline to day 84 on a semi-quantitative mycobacterial growth scale. Other endpoints included sputum conversion, 6-minute walk distance, and adverse events. Measurements and Main Results Modified intent-to-treat population included 89 (LAI=44; placebo=45) patients. Average age was 59 years, 88% were female, 92% were Caucasian; 80 and 59 patients completed study drug dosing during the double-blind and open-label phases, respectively. Primary endpoint was not achieved (P=0.072); however, a greater proportion of the LAI group demonstrated >/=1 negative sputum cultures (32% [14/44] vs. 9% [4/45]; P=0.006) and improvement in 6-minute walk test (+20.6 vs. -25.0 meters; P=0.017) at day 84. Treatment effect was predominantly in patients without cystic fibrosis with MAC and was sustained 1 year post-LAI. Most adverse events were respiratory and in some patients led to drug discontinuation. Conclusions Although the primary endpoint was not reached, LAI added to a multi-drug regimen produced improvements in sputum conversion and 6-minute walk distance vs. placebo with limited systemic toxicity in patients with refractory MAC lung disease. Further research is needed. Clinical trial registration available at www.clinicaltrials.gov, ID NCT01315236.