The efficacy of 6 wk of therapy with oral ICI 204,219, a selective leukotriene D4 (LTD4) receptor antagonist, was evaluated in subjects with moderate asthma during a multicenter, double-blind, randomized, placebo-controlled, dose-ranging study. Subjects who entered the trial had been chronically treated for asthma with beta agonist alone or in combination with theophylline. Subjects were randomized to treatment with twice daily doses of ICI 204,219 (5, 10, or 20 mg) or placebo if they had an FEV1 between 40 and 75% of predicted values without bronchodilator therapy and a daytime asthma score > 10 (range 0 to 21 per wk) for 7 consecutive d. Efficacy was evaluated from the results of symptom assessments, pulmonary function tests, and rescue medication use. Of 276 subjects randomized to treatment, 266 (10 mg, n = 66; 20 mg, n = 67; 40 mg, n = 67; placebo, n = 66) were analyzed for efficacy. Diary card assessments showed that treatment with increasing doses of ICI 204,219 linearly improved five efficacy criteria without increasing the number or severity of adverse events. The 40 mg dose was more effective than placebo (p < 0.05) in reducing nighttime awakenings, first morning asthma symptoms, the daytime asthma score, and albuterol use and in increasing evening peak expiratory flow (PEF) rates as well as FEV1. Compared with baseline measurements, the 40 mg dose decreased awakenings by 46%, albuterol use by 30%, and daytime symptoms by 26% and increased FEV1 by 11%. ICI 204,219 improves objective and subjective measures of asthma severity in moderately ill asthmatic subjects and may provide a new treatment option for the disease.