AbstrAct Introduction: Mycobacterium avium complex (MAC) is a leading cause of pulmonary disease (PD), even in those with intact immunity, representing about 30% of the cases of pleuropulmonary mycobacterial infection. Based on previous studies, macrolides are the only agents used in the treatment of MAC disease for which there is a correlation between in vitro susceptibility and in vivo (clinical) response. However, resistance develops rapidly if single-agent treatment is used. Data regarding treatment of macrolide-resistant MAC (MRMAC) and multidrug-resistant MAC (MDRMAC) are sparse. Case summary: A 50-year-old, HIV-negative white man, weighing 53.6 kg, with severe chronic obstructive pulmonary disease and bronchiectasis was initially on treatment for MAC-PD and MRMAC. The patient was followed between 1999 and 2006. His treatment history revealed that in addition to the multiple drugs administered during the course of his illness, thalidomide, interferon-γ, and mefloquine were also administered. The patient died ~7 years later due to respiratory failure and overwhelming infection Conclusions: This case report describes the use of mefloquine as adjunct treatment in an HIV-negative patient with MDRMAC-PD and discusses the associated outcomes of drug resistance.