Background: Interventions against acute exacerbations (AEs) of chronic obstructive pulmonary disease (COPD) are increasingly called for to reduce morbidity, mortality and costs. OM-85, a detoxified immunoactive bacterial extract, has been shown to prevent recurrent exacerbations of bronchitis and COPD. Objectives: It was the aim of this study to demonstrate the protective effect of OM-85 against recurrent bronchitic exacerbations in patients with chronic bronchitis or mild COPD. The primary end point was the mean rate of AEs occurring within the study period. Methods: This double-blind multi-centre study enrolled adult outpatients >40 years old of both sexes with a history of chronic bronchitis or mild COPD at the time of an AE. The treatment consisted of one capsule of OM-85 or placebo per day for 30 days, followed by three 10-day courses for months 3, 4 and 5, with a 6-month study duration and monthly control visits. Results: One hundred and forty-two patients were treated with OM-85 and 131 received placebo. By the end of the treatment period, the mean number of AEs in the OM-85 group was 0.61 per patient versus 0.86 per patient in the placebo group (–29%; p = 0.03). The difference between treatments was most notable in patients with a history of current or past smoking (–40%; p < 0.01). No serious adverse events were attributed to the medication and no significant laboratory changes were reported. Conclusions: OM-85 significantly reduced the frequency of AEs in patients with a history of chronic bronchitis and mild COPD and was well tolerated. This study confirms the findings of previous trials conducted in elderly patients with chronic bronchitis or COPD.