Background/Aims: Although increased mortality has been reported among people with Methods: We included Medicare beneficiaries aged ≥65 years with bronchiectasis (01/2006-12/2014). We limited our cohort to new MAC-PD therapy users. MAC-PD therapy was defined as ≥60-day prescriptions for a macrolide plus ≥1 other MAC-PD antibiotic. Guideline-based therapy (GBT) included a macrolide, ethambutol, and/or rifamycin. Using Cox proportional hazard models, we calculated adjusted hazard ratios (aHR) for death up to 3 years after therapy start between the following groups: (1) 2007 GBT versus non-GBT; (2) 2020 GBT versus non-GBT; and (3) macrolide-ethambutol-rifamycin (3-drug) versus macrolide-ethambutol (2-drug). Results: We identified 4820 new MAC-PD therapy users, of whom 866 (17.9%) were deceased within 3 years of therapy initiation. Of 3040 (63.1%) beneficiaries prescribed 2007 GBT, 472 (15.5%) were deceased by 3 years, compared to 394 (22.1%) of 1780 (36.9%) prescribed non-GBT (aHR 0.82; 95% confidence interval [CI], .72-.94). We observed a similar trend for 2020 GBT versus non-GBT (aHR 0.81; 95% CI, .70-.94]). Three-year-mortality was similar between those starting 3-drug versus 2-drug regimens (aHR 0.89; 95% CI, .74-1.08]). Conclusions: Among Medicare new MAC-PD therapy users, 3-year-mortality was higher in those prescribed non-GBT regimens compared to GBT regimens. Whether this finding suggests improved efficacy of GBT and/or differential characteristic of those using non-GBT regimens deserves further study.