Abstract Regular use of β 2-agonists might result in increased bronchial hyper-responsiveness (BHR) and decreased forced expiratory volume in 1 sec (FEV 1). It has been suggested that these possible detrimental effects are not a real deterioration of the disease but that it might be only a transient (rebound) effect shortly after discontinuing this regular use. Moreover these effects are thought to occur especially during short-acting and not during long-acting β 2-agonists use. The aim of this study was to investigate whether a rebound effect (a pharmacological deterioration effect diminishing after several hours) in FEV 1 and PC 20 (concentration of histamine causing a 20% fall in FEV 1 with regard to baseline) occurred after cessation of regular use of β 2 -agonists and whether this occurred both after short-acting and long-acting β 2 -agonists. Allergic asthmatic patients ( n=134) were randomly allocated to the use of a short-acting (salbutamol) a long-acting β 2-agonist (formoterol) or placebo for 12 weeks (double-blind double-dummy). No other asthma medication was allowed including inhaled corticosteroids. At the start and every 4 weeks later FEV 1 and PC 20 were measured each time at least 12 h after the last doses of study medication which is in the possible rebound period. To investigate whether a (transient) rebound effect occurred parameters were additionally measured at least 72 h later after discontinuation of the study medication. After 12 weeks of short-acting β 2-agonist use a drop was seen in FEV 1 from 85·6(±2·21)% predicted to 78·8 (±2·9)% predicted measured 15 h (median) after the last doses of medication. This was significantly different compared to placebo. When measured 168 h (median) later FEV 1 recovered to 85·5 (±2·4)% predicted comparable to baseline. PC 20 decreased with −1·17 (±0·44) doubling dose after 12 weeks of short-acting β 2-agonist use measured 15 h after the last doses of medication which was significantly different compared to placebo. However 168 h later PC 20 recovered slightly with +0·55 (±0·34) doubling dose but this value was still lower compared to placebo. In contrast during long-acting β 2 -agonist and placebo use no significant changes were seen. In conclusion the use of short-acting β 2 -agonists resulted in a transient (rebound) effect in FEV 1 while the effects on PC 20 may point to a real deterioration of the disease. Long-acting β 2-agonist and placebo use showed no changes. We conclude that a mono-therapy of short-acting and not of long-acting β 2-agonists might have deleterious effects in asthma.