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CysLT1 antagonists are effective for a subset of patients with asthma; however, there has been no good way to predict a given patient's response. We examined the interaction between the clinical response to a cysLT1 antagonist, pranlukast, and DNA sequence variant A(-444)C in leukotriene C4 synthase (LTC4S) gene in Japanese patients with moderate asthma. The frequency of LTC4S C(-444) allele was 21.6% in the Japanese general population (n = 171) and 19.4% in the asthmatic subjects (n = 349). A 4-week prospective, open trial of pranlukast (225 mg twice daily) was performed in 50 patients with moderate asthma who had been well controlled with inhaled corticosteroid (beclomethasone 400–800 μg/day or fluticasone 200–400 μg/day). The C(-444) allele carriers (n = 16) responded better to pranlukast compared to the A(-444) allele homozygotes (n = 31) [14.3 ± 5.3% vs. 3.1 ± 2.4% improvement of forced expiratory volume in one second (FEV1), P< 0.01], while LTC4S genotype-stratified response to inhaled β-agonist salbutamol (200 μg) was not observed (17.5 ± 2.1% vs. 18.7 ± 2.2% improvement of FEV1). Univariate analysis demonstrated that the better response to pranlukast (more than 10% improvement of FEV1) was correlated with LTC4S genotype (P< 0.01) and pretreatment airway reversibility to salbutamol (P< 0.01), but not with sex, age, atopic status, urinary leukotriene E4 excretion rate, or daily dose of inhaled corticosteroid. Furthermore, multivariate regression analysis suggested that LTC4S genotype and the bronchodilatory effect of salbutamol were independent variables to predict the clinical response to pranlukast (P< 0.05). We conclude that LTC4S genotype is predictive of the clinical response to a cysLT1 antagonist, pranlukast, in Japanese patients with moderate asthma.