Background: Acute exacerbations of COPD reflect in part an inappropriate host response to abnormal bacterial colonization. Orally administered inactivated nontypeable Haemophilus influenzae (NTHi) can drive a specific T-cell response that by promoting intrabronchial phagocytosis down-regulates bronchus inflammation. Methods: Subjects with recurrent exacerbations of COPD were studied in a randomized, multicenter, double-blind, placebo-controlled trial, to test efficacy of an NTHi oral immunotherapeutic (HI-164OV). This report describes the outcome in 38 subjects with severe COPD defined as having an FEV₁ ≤ 50% of predicted normal. Results: Exacerbations defined as an increase in volume and purulence of sputum were reduced by 16% (not significant) in the active group. However, moderate-to-severe exacerbations (defined as requiring corticosteroid therapy) were reduced by 63% (P=.05). The proportion with any acute exacerbation was little changed with treatment, but the proportion with episodes requiring corticosteroid therapy was reduced by 56% (P=.07). The mean duration of episodes was reduced by 37% (P=.01) and prescribed courses of antibiotics were reduced by 56% (P=.03) following therapy. Exacerbations requiring admission into hospital were reduced by 90% (P=.04) in the active group. No specific adverse effect was detected. Conclusions: Treatment of severe COPD with frequent exacerbations with HI-164OV was safe and effective, especially with respect to reduction in parameters of severity.