Objective　To study the effect of genetic polymorphism of leukotriene C4 synthase (LTC4S) and 5-lipoxygenase (ALOX5) on efficacy of leukotriene receptor antagonist (LTRA) in children with moderate persistent asthma. Methods Seventy-two children with moderate persistent asthma who visited the out-patient clinic of Shanghai Children’s Medical. Center from June 2011 to June 2013 were divided into two groups, each of which first had ICS or LTRA+ICS for twelve weeks and then had the other for another twelve weeks. Polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) was used to assess the genetic polymorphism of LTC4S RS730012 and ALOX5 RS2115819. Pulmonary function, clinical symptoms and C-ACT score were evaluated before and after treatment. Results After the treatment with LTRA, 75% forced expiratory flow (FEF75) was improved more significantly in patients with A/C or C/C genotype at LTC4S (RS730012) locus than in patients with A/A genotype. After the treatment with LTRA+ICS, there was no difference of pulmonary function among patients with different genotypes at ALOX5 (RS2115819). Conclusions The SNP of LTC4S (RS730012) is associated with the efficacy of montelukast in asthmatic patients because of the improvement of small airway function.