Objective To investigate the association between environmental factors and nonsyndromic cleft lip and palate (NSCLP), and to explore the interaction of main risk factors in Chinese Guangdong population. Methods A hospital-based case-control study was used. NSCLP children were selected from Cleft Lip amp; Palate Treatment Centre of Second Affil iated Hospital of Medical College of Shantou University between September 2009 and March 2010 as cases. And controlswere chosen from other departments in the same hospital during the same period. The parents of cases and controls were inquired regarding the risk factors and the answers were filled in a unification questionnaire by physicians. These data were analysed with chi-square test and multivariate unconditional logistic regression analysis. Results A total of 105 cases and 110 controls with a mean age of 2.2 years and 3.0 years, respectively, were enrolled. Multivariate logistic regression analysis revealed that genetic family history (OR=4.210, P=0.039), mothers’ abnormal reproductive history (OR=2.494, P=0.033), early pregnancy medication (OR=3.488, P=0.000), and maternal stress (OR=3.416, P=0.011) were risk factors. There were positve interactions between genetic family history and mothers’ abnormal reproductive history as well as early pregnancy medication. Conclusion Certain influencing factors including genetic family history, mothers’ abnormal reproductive history, early pregnancy medication, and maternal stress are associated with NSCLP among Chinese Guangdong population. This study suggests that it may reduce the incidence rate of NSCLP through environmental intervention.