ObjectiveTo study the relationship between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) in eastern Guangdong for the prevention of NSCLP. MethodsA 1:1 retrospective case-control study was carried out. Data from 479 children with NSCLP who accepted comprehensive care in our center were recruited as cases from April 2010 to April 2013. An equal number of controls were recruited from pediatrics during the same period. Then we conducted face-to-face interviews with both parents using a structural questionnaire to identify the relationship between NSCLP and environmental risk factors. ResultsUnivariate Chi-square analysis identified 23 factors (P<0.05) as being significantly related to NSCLP. Stepwise multiple logistic regression analyses demonstrated that there were 16 factors significantly associated with this disease. Being male (OR=0.609), parental childbearing age of 25–29 years (ORfather=0.633; ORmother=0.469), higher parental education level (high school or greater) and folic acid supplementation (OR=0.360) were protective factors against NSCLP. However, positive family history of NSCLP (OR=54.132), positive maternal abortion history (OR=3.698), high or low parental age at time of childbirth, poor maternal education level (primary school) (OR=2.258), maternal common cold during pregnancy (OR=1.464), and drug use during pregnancy (OR=3.364) were significant risk factors for NSCLP. ConclusionThe findings are beneficial for researchers to understand the etiology of NSCLP and to lay a solid foundation for the prevention of NSCLP in eastern Guangdong through educational programs to teach parents about the benefits of folic acid supplementation, adequate parental age at childbirth (25–29 years), higher parental education level (high school or higher), and the dangers of common cold and drug use during the first trimester of pregnancy, positive family history and maternal abortion history.