To investigate the effects of interactions among environmental factors, bone morphogenetic protein-4 (BMP4) and transforming growth factor beta-3 (TGF-β(3)) polymorphisms on nonsyndromic cleft lip and cleft palate (NSCLP). The data of environmental exposures were collected with questionnaires. Genotypes were determined with techniques of polymerase chain reaction-restriction fragment length polymorphism. Interactions between genes, environmental factors and NSCLP were analyzed using multifactor dimensionality reduction (MDR) method. The interactions were validated by logistic regression analysis. There was no correlation between three single nucleotide polymorphism (SNP) associated with NSCLP. The developmental accident of NSCLP had higher risk in the interaction between BMP4 T538C, maternal passive smoking and infection in first trimester pregnancy, as well as in the interaction of six factors between TGF-β(3) G15572-, maternal passive smoking, infections, multivitamin supplement in the first trimester pregnancy, paternal smoking and high risk drinking before realizing pregnancy than in other interactions of environmental factors. The results could be validated by logistic regression analysis. The NSCLP is induced by the interactions between genes and environmental risk factors.