Abstract Background Mycobacterium avium complex lung disease (MAC-LD) is an infection that is increasing in frequency, associated with substantial disease burden, and often refractory to treatment. Amikacin liposome inhalation suspension (ALIS) is the first therapy approved for refractory MAC-LD. In the CONVERT study of adult patients with refractory MAC-LD, adding ALIS to a multidrug background regimen showed evidence of MAC infection elimination in sputum by month 6, which was maintained in most patients through the end of treatment (≤ 12 months post-conversion). This study assessed changes in healthcare resource utilization (HCRU) among patients initiating ALIS in real-world settings. Methods This retrospective cohort study of the All-Payer Claims Database (October 2018–April 2020) included patients aged ≥ 18 years with ≥ 1 pharmacy claim for ALIS and ≥ 12 months of continuous health plan enrollment pre- and post-ALIS initiation. Respiratory disease-related (and all-cause) HCRU (hospitalizations, length of stay [LOS], emergency department [ED] visits, and outpatient office visits) were compared 12 months pre- and post-ALIS initiation. Outcomes were reported at 6-month intervals; 0–6 months pre-ALIS initiation was the reference period for statistical comparisons. Results A total of 331 patients received ALIS, with HCRU highest in the 6 months pre-ALIS initiation. Compared with 26.9% during the reference period, respiratory-related hospitalizations decreased to 19.3% (P < 0.01) and 15.4% (P < 0.0001) during 0–6 and 7–12 months post-ALIS initiation, respectively. Mean number of respiratory disease-related hospitalizations per patient/6-month period decreased from 1.0 (reference period) to 0.6 (P < 0.0005) at both timepoints post-ALIS initiation. A similar pattern was observed for all-cause hospitalizations and hospitalizations per patient/6-month period (both P < 0.005). Reductions in all-cause and respiratory disease–related LOS post-ALIS initiation were significant (both P < 0.05). ED visits were few and unchanged during the study. Significant reductions per patient/6-month period in all-cause and respiratory-related outpatient office visits were observed post-ALIS initiation (all P < 0.01). Conclusions In this first real-world study of ALIS, respiratory disease-related (and all-cause) hospitalizations and outpatient visits were reduced in the 12 months following ALIS initiation. The results of this study provide HCRU-related information to better understand the impact of initiating ALIS treatment. Trial registration Not appliable.