Recurrent exacerbations are a major cause of morbidity and medical expenditure in patients with asthma. Various exogenous and endogenous factors are thought to influence the level of asthma control, but systematical data on the involvement of these factors in the recurrence of asthma exacerbations are scarce. In this study, 13 clinical and environmental factors potentially associated with recurrent exacerbations were investigated in 136 patients with difficult-to-treat asthma. Patients with more than three severe exacerbations (n = 39) in the previous year were compared with those with only one exacerbation per year (n = 24). A systematic diagnostic protocol was used to assess 13 potential risk factors. Factors significantly associated with frequent exacerbations included: severe nasal sinus disease (adjusted odds ratio (OR) 3.7); gastro-oesophageal reflux (OR 4.9); recurrent respiratory infections (OR 6.9); psychological dysfunctioning (OR 10.8); and obstructive sleep apnoea (OR 3.4). Severe chronic sinus disease and psychological dysfunctioning were the only independently associated factors (adjusted OR 5.5 and 11.7, respectively). All patients with frequent exacerbations exhibited at least one of these five factors, whilst 52% showed three or more factors. In conclusion, the results show that recurrent exacerbations in asthma are associated with specific co-morbid factors that are easy to detect and that are treatable. Therapeutic interventions aimed at correcting these factors are likely to reduce morbidity and medical expenditure in these patients.