Tolerance to the bronchoprotective effects by long-acting beta2-agonists (LAB) in patients with asthma is not prevented by inhaled corticosteroids (ICS). This study examined whether oral prednisolone can restore the bronchoprotective effects of formoterol in 24 patients with persistent asthma already treated with ICS (at least 800 microg budesonide x day(-1) or equivalent) and LAB, using a parallel-group design. During a 2-week run-in period and during the study, patients used formoterol 12 microg twice daily by Turbuhaler, instead of their own LAB. At baseline and at the end of 7-days treatment with oral placebo or prednisolone (30 mg x day(-1)), provocative concentration of histamine causing a 20% fall in forced expiratory volume in one second (PC20 histamine) was measured on two separate days after randomized single-dose inhalation of placebo (postP) or formoterol (postF). In addition, PC20postF was measured 24 h after starting oral treatment. The protective effect by formoterol at baseline and during treatment was calculated as the difference between the logs of PC20postP and PC20postF. The mean+/-SEM in doubling dose (DD) bronchoprotective effect at baseline was 0.8+/-0.4 DD in the placebo group and 1.0+/-0.4 DD in the prednisolone group. At the end of the treatment period, the protective effect changed to 1.0+/-0.5 DD and 0.8+/-0.6 DD in the placebo and prednisolone treated groups, respectively. This change was not different between the groups (p > 0.4). In conclusion, the bronchoprotective effect by formoterol is not influenced by 1 week prednisolone treatment in patients with asthma who are using regular inhaled corticosteroids and long-acting beta2-agonists. These findings indicate that tolerance to long-acting beta2-agonists cannot be restored by oral steroid therapy.