Purpose Macrolides are a recommended treatment option for severe asthma, but data for “difficult-to-treat” asthma, the asthma-COPD “overlap” syndrome, and treatment duration beyond one year are lacking. We present long-term data from community practice experience providing insights for practice and research. Methods We report data from (1) baseline (pre-treatment) chart review of antibiotic-treated asthma patients and (2) follow-up telephone interviews documenting severe exacerbations (NIH criteria), Asthma Control Test (ACT) scores, and asthma controller use at baseline and follow-up, analyzed using a “before-after” model. Results A total of 101 patients (mean age 55.6 years (Sd 16.8), 66 females) were included. None had ever taken high dose inhaled corticosteroids and 79 (78.2%) were severely uncontrolled (ACT score ≤15) before treatment. Coexisting COPD was present in 62 (61.4%) patients. Azithromycin or azithromycin plus doxycycline was primarily prescribed with a median treatment duration of 12 months and median follow-up duration of 22 months. Severe exacerbations in the month before treatment occurred in 50.5% vs 17.8% at follow-up (P<0.0001). Mean ACT score increased from 12.2 to 20.6 (P<0.0001). The number of patients taking controller medications decreased (P<0.0001 for inhaled corticosteroids; P<0.001 for long-acting beta agonist/long-acting muscarinic antagonist; P<0.05 for leukotriene receptor antagonists). Of the 79 severely uncontrolled patients, 51 (64.6%) became controlled at follow-up, and of these 51, 27 (52.9%) continued to take antibiotics while 24 (47.1%) had discontinued antibiotics earlier yet remained controlled. Conclusion Antibiotic treatment may be beneficial in a significant proportion of “difficult to treat” asthma patients beyond one year, including some patients with the overlap syndrome and/or who fail to meet criteria for refractoriness.