Background: PCR studies have demonstrated evidence of Mycoplasma pneumoniae and Chlamydophila pneumoniae in the lower airways of patients with asthma. Objective: To test the hypothesis that clarithromycin would improve asthma control in individuals with mild-to-moderate persistent asthma that was not well controlled despite treatment with low-dose inhaled corticosteroids. Methods: Adults with an Asthma Control Questionnaire score ≥1.5 after a 4-week period of treatment with fluticasone propionate were entered into a PCR-stratified randomized, controlled trial to evaluate the effect of 16 weeks of either clarithromycin or placebo, added to fluticasone, on asthma control in individuals with or without lower airway PCR evidence of M pneumoniae or C pneumoniae. Results: A total of 92 participants were randomized. Twelve (13%) subjects demonstrated PCR evidence of M pneumoniae or C pneumoniae in endobronchial biopsies; 80 were PCR-negative for both organisms. In PCR-positive participants, clarithromycin yielded a 0.4 ± 0.4 unit improvement in the Asthma Control Questionnaire score, with a 0.1 ± 0.3 unit improvement in those allocated to placebo. This between-group difference of 0.3 ± 0.5 (P = .6) was neither clinically nor statistically significant. In PCR-negative participants, a nonsignificant between-group difference of 0.2 ± 0.2 units (P = .3) was observed. Clarithromycin did not improve lung function or airway inflammation but did improve airway hyperresponsiveness, increasing the methacholine PC20 by 1.2 ± 0.5 doubling doses (P = .02) in the study population. Conclusion: Adding clarithromycin to fluticasone in adults with mild-to-moderate persistent asthma that was suboptimally controlled by low-dose inhaled corticosteroids alone did not further improve asthma control. Although there was an improvement in airway hyperresponsiveness with clarithromycin, this benefit was not accompanied by improvements in other secondary outcomes.