Fifteen hospitalized asthmatic children (8 to 18 years old) completed a 2-week randomized, parallel, double-blind placebo-controlled comparison of combination methylprednisolone and placebo troleandomycin, prednisone and troleandomycin (P-TAO) or methylprednisolone-TAO (MPn-TAO). Troleandomycin (250 mg once daily or every other day) and glucocorticoid doses were reduced by a standard protocol. Symptom scores, blood chemistries, pulmonary function tests, airway response to methacholine, and glucocorticoid pharmacokinetics were compared. In each group, a steroid dose reduction of 50% was achieved without a deterioration in symptom scores. Methacholine response was unchanged in all five on methylprednisolone alone, but decreased 3-fold to 30-fold in two of five on combination P-TAO, and four of five on combination MPn-TAO. Troleandomycin decreased MPn clearance by an average of 62% but did not alter prednisolone clearance. Low-dose TAO combined with MPn has a significant effect on methylprednisolone clearance in children, an effect equivalent to that reported with higher dose TAO (1000 mg/d) therapy. In addition, this preliminary study suggests that TAO may decrease bronchial hyperresponsiveness to methacholine in severely asthmatic children.