Objective To study the association of TGF-α gene polymorphism and non-syndromic cleft lip with cleft palate in Shandong province. Methods Polymerase chain reaction combined with restrict enzyme digestion was used to detect the target gene variation in 98 patients with non-syndromic cleft lip with cleft palate and 101 healthy controls. Results The C2 allele frequency in patients with non-syndromic cleft lip with cleft palate was significantly higher than that in healthy controls. The genotype frequency in patients with positive family history was significantly higher than that without positive family history. Conclusion TGF-α gene polymorphism is closely associated with non-syndromic cleft lip with cleft palate in Shandong, especially in patients with positive family history.