Sixteen severe, corticosteroid-dependent yet resistant outpatient asthmatics were treated with troleandomycin (TAO), a macrolide antibiotic, in an attempt to both induce a clinical remission and reduce methylprednisolone requirements. Within the first 2 wk of initiating TAO therapy, 50% of the patients experienced a greater than 20% increase in forced expiratory volume in 1 sec (FEV1) and 80% noted a greater than 20% increase in forced vital capacity between 25% and 75% (FVC 25%-75%). Maximal increases in FEV1 and FVC 25%-75% were noted in all patients within the first 6 wk on TAO and methylprednisolone. There was a concomitant clinical improvement in all patients. Corticosteroid-induced side effects, gastrointestinal tract discomfort, and elevated serum glutamic pyruvic transaminase (SGPT) were common yet generally transient during TAO and methylprednisolone therapy. After a 4- to 18-mo follow-up 15/16 patients were well-controlled on TAO and methylprednisolone. Methylprednisolone requirements were reduced at least four- to fivefold in most patients during TAO therapy. Normal morning serum cortisol levels were documented after varying intervals in most patients when both TAO (250 mg) and methylprednisolone (4 to 16 mg) could be reduced to alternate-day administration. Only one patient was forced to discontinue therapy due to side effects. The present study extends the effectiveness of TAO therapy to ambulatory asthmatics, establishes a clinical strategy that maximizes benefit/risk factors, and provides practical guidelines for the long-term use of TAO and methylprednisolone.