Objective : Orofacial clefts such as cleft palate (CP) and cleft lip (CL) and/or cleft palate (CL/P) are the most common congenital anomalies of the head and neck. The aims of the present study were to evaluate the possible association between CDH1 (rs11642413 and rs16260) and MSX1 (rs12532 and rs3775261) gene polymorphisms and nonsyndromic cleft lip and/or cleft palate (NS-CL/P) in a sample of the Iranian population. Design and Setting : This case-control study was performed on 100 subjects with NS-CL/P and 100 healthy unrelated control subjects. Tetra amplification refractory mutation system-polymerase chain reaction and multiplex polymerase chain reaction were used to detect the single-nucleotide polymorphisms. Results : There was a significant difference between NS-CL/P subjects and control subjects regarding CDH1 rs16260 C > A polymorphism, and the rs16260 AC as well as the rs16260 AA genotypes were associated with NS-CL/P susceptibility (odds ratio [OR] = 3.02, 95% confidence interval [CI] =1.51-6.00, P = .001; and OR = 8.05, 95% CI = 1.72-37.75, P = .002, respectively). No significant difference was found between the groups regarding CDH1 rs11642413 polymorphism. Although MSX1 rs3775261 polymorphism was not a risk factor for the disease, the rs12532 AG and rs12532 GG genotypes were associated with NS-CL/P risk (OR = 2.82, 95% CI = 1.55-5.15, P = .001; and OR = 8.42, 95% CI = 2.26-31.29, P = .004, respectively). Conclusion : Our data suggest that CDH1 and MSX1 gene polymorphisms are risk factors for susceptibility to NS-CL/P in a sample of the Iranian population. Larger studies are required to validate our findings.