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Clinical recurrence of Mycobacterium avium complex (MAC) pulmonary disease occurs in 10 to 40% of patients treated for this disease process. Episodes of clinical recurrence may represent true relapse from the same MAC strain or reinfection with a new strain.The purpose of this study was to investigate the clinical implications of separating patients into these two groups.This retrospective study evaluated patients with a clinical recurrence of MAC pulmonary disease at our institution from 2000 to 2012. Isolates were genotyped using pulsed-field gel electrophoresis to differentiate relapse versus reinfection. Change in macrolide susceptibility was also analyzed.In our cohort, 25% of patients suffered a clinical recurrence. Of the 46 included patients, 25 (54%) suffered a true relapse and 21 (46%) had a reinfection. Median time between completion of therapy and clinical recurrence was significantly lower in the relapse group compared with the reinfection group (210 d vs. 671 d; P = 0.004). The measured convalescent macrolide minimum inhibitory concentrations were significantly more likely to increase in the relapse group compared with the reinfection group (80 vs. 33%; P = 0.002). No differences in clinical outcomes were observed between the two groups at conclusion of the study.Our findings suggest that patients with true relapse of MAC pulmonary disease present earlier than those with reinfection. Routine use of pulsed-field gel electrophoresis in the management of clinical recurrences may be beneficial, as those suffering a relapse are more likely to have increasing macrolide minimum inhibitory concentrations than those with reinfection.