Objective: To study the mutual effect of EPHA3 gene polymorphism, folic acid intake in early pregnancy, and the occurrence of non-syndromic cleft lip with or without cleft palate, so as to provide the oretical basis for a etiological study on non-syndromic cleft lip with or without cleft palate. Methods: A total of 195 patients and 170 controls were included.The candidate site rs7650466 was genotyped by Snapshot technique.The correlation with folic acid intake in early pregnancy was analyzed. Result: The rs7650466 T allele was highly associated with the pathogenesis of non-syndromic cleft lip with or without cleft palate(OR=0.2472, 95%CI=0.1567-0.3899, P=1.851×10^-9). The T allele had protective effects.Folic acid intake in early pregnancy, and its interaction with EPHA3 gene, were associated with the pathogenesis of this disease(P<0.05). Conclusions EPHA3 gene, folic acid intake during the first trimester, and theinteractionsare associated with the pathogenesis of non-syndromic cleft lip with or without cleft palate.