Although most patients with asthma improve with currently available drugs, there appears to be a subset of patients with asthma resistant to intensive treatment, including large doses of systemic corticosteroids. In 10 patients with asthma difficult to treat, a double-blind, placebo-controlled, crossover study was performed to evaluate whether long-term, continuous subcutaneous infusion of large doses of salbutamol, in addition to steroids, could improve pulmonary function, compared with intermittent nebulization of salbutamol. Four weeks of administration of large doses (greater than 14 mg/day) of beta 2-agonists were well tolerated, elicited a significant decrease of corticosteroid consumption (p less than 0.01), and were associated with an improvement in pulmonary function (p less than 0.01), compared with run in or the placebo administration period. Mean morning and evening peak expiratory flow rates were similar during all periods, and the variability between morning and evening peak expiratory flow rates was only slightly and nonsignificantly reduced during the period when salbutamol was administered subcutaneously. Both nebulized and subcutaneous salbutamol elicited similar metabolic and muscular side effects, but these untoward reactions never caused any patient to stop the treatment. Local infection at the injection site was observed in two of 10 patients with continuous subcutaneous infusion. Tachyphylaxis to beta 2-agonist, as measured by the reversibility of FEV1 to inhaled salbutamol 12 hours after the end of each period, did not occur. In conclusion, large doses of beta 2-agonist administered to patients with severe, chronic, and steroid-dependent asthma were able to improve respiratory function and to decrease corticosteroids requirements.