Long-acting beta 2-agonists (LBA) have become an important therapeutic strategy in the treatment of asthma. There is, however, debate whether LBA increase the risk of asthma exacerbations (AE). We studied whether the risk of AE was increased in patents starting LBA therapy and whether the risk was associated with severity. Patients, aged 5-49 years, who were firstly prescribed LBA between 1992 and 1995, and who had at least two consecutive prescriptions of LBA, were selected from the PHARMO-RLS database. The exposure period was the interval between the first and last dispensing of the first exposure episode. The year before the onset was the control period. Single short courses of oral glucocorticosteroids or antibiotics were used as proxy indicators for AE. Severity indicators, assessed in the 6 months before initiation of LBA, were used to classify patients’ severity. A total of 788 patients met the inclusion criteria (men: 45.1%, median age: 35). The incidence rate of AE increased significantly (p < 0.001) with severity from 1.7 to 2.4 and 1.1 to 2.7 AE per person year in index and control period, respectively. The risk was merely elevated among patients who start LBA therapy without being treated with other anti-asthma drugs before (RR 1.4, 95% CI 1.0-2.2). First starters of LBA showed no overall change in incidence of AE when compared with the year before starting treatment. A total of 6.9% of patients used LBA as step-one therapy. These patients suffer, in contrast to the whole population, a 40% increased risk of having AE. Although this could be due to confounding, we recommend being reluctant to prescribe LBA to patients who have not been treated before with other anti-asthma drugs.