To identify the interactions among two loci (C641A and G15572-) of transforming growth factor beta 3 (TGFbeta3), and exposures in pregnancy with cleft lip with/without cleft palate (CL/P), a hospital-based case-control study was conducted. Associations among offspring polymorphisms of TGFbeta3 C641A and G15572-, paternal smoking, paternal high-risk drinking, maternal passive smoking, and maternal multivitamin supplement with CL/P were analyzed by logistic regression analysis, and the results showed that maternal passive smoking exposures and maternal multivitamin use were associated with the risk of CL/P but offspring polymorphisms of TGFbeta3 C641A and G15572-, paternal smoking, and paternal high-risk drinking were not. Interactions among these variables were analyzed using the multifactor dimensionality reduction method, and the results showed that the two-factor model, including maternal passive smoking and TGFbeta3 C641A, among all models evaluated had the best ability to predict CL/P risk with a maximum cross-validation consistency (9/10) and a maximum average testing accuracy (0.5892; p = 0.0010). These findings suggested that maternal passive smoking exposure is a risk factor for CL/P, whereas maternal multivitamin supplement is a protective factor. The polymorphism of TGFbeta3 C641A participates in interaction effect for CL/P with environmental exposures, although the polymorphism was not associated with CL/P in single-locus analysis, and synergistic effect of TGFbeta3 C641A and maternal passive smoking could provide a new tool for identifying high-risk individuals of CL/P and also an additional evidence that CL/P is determined by both genetic and environmental factors.