The objective of this study was to observe the outcomes of adding an antimicrobial treatment to a conventional treatment regime in horses with severe equine asthma in a clinical setting. Eleven client-owned horses with a history consistent with severe equine asthma, increased respiratory effort and nostril flaring, ≥ 20% neutrophils on bronchoalveolar lavage (BAL), and a positive tracheal wash (TW) bacterial culture were treated with environmental management, corticosteroids, and bronchodilators. Six horses were also treated with an antimicrobial (principal group), while the other 5 were administered saline as a placebo (control group). Treatment with antimicrobials significantly improved the post-treatment clinical score of the principal group compared with the pre-treatment score, whereas no significant difference occurred in the control group. The principal group also had significantly less neutrophil myeloperoxidase (MPO) activity post-treatment than pre-treatment, with a median difference of -0.39 units/[protein] in the principal group and a median difference of -0.21 units/[protein] in the controls. There was no difference in MPO activity pre- versus post-treatment in the control group. No differences were noted in the intra-group comparisons of pre- versus post-treatment BAL neutrophil counts, mucus scores, and concentrations of interleukin-8 (IL-8) or tumor necrosis factor-alpha (TNF-α) in bronchoalveolar lavage fluid (BALF) in either group. There were no differences found in the inter-group comparisons of the principal versus controls for each of the pre- and post-treatment time periods for BAL neutrophil count, mucus score, clinical scores, MPO activity, and IL-8 or TNF-α concentrations. The role of airway bacteria in horses with severe equine asthma requires further investigation as antimicrobial therapy improved post-treatment clinical scores and decreased MPO activity in the group of horses studied, but did not affect other measures of airway inflammation.