Oral squamous cell carcinoma (OSCC) is the most common epithelial malignancy in the oral cavity. The risk of the development of OSCC is high in Fanconi anemia (FA) patients owing to the DNA repair deficiency in somatic cells. EGFR, and CTNNB1 genes are suggested to be effective in development of OSCC. EGFR has been reported to have higher expression in OSCC, there are limited studies of EGFR and CTNNB1 gene polymorphisms in the development of OSCC. Therefore, we aimed to investigate the potential connection between EGFR rs845561 and CTNNB1 rs3864004 gene polymorphisms, and OSCC and FA. We performed polymerase chain reaction (PCR)/sanger sequencing for detection of the variations in these regions. EGFR rs845561, and CTNNB1 rs3864004 gene variants were compared between OSCC patients, and controls, no significant difference was detected (P>0.05). The EGFR rs845561 C allele frequency was lower in OSCC patients who had lymh node metastasis (P= 0.001), a significant association was detected between the EGFR rs845561 T allele frequency, and tumor perineural invasion (P= 0.05) in OSCC patients. CTNNB1 rs3864004 A allele frequency was associated with increased tumor invasion in OSCC patients (P= 0.01). The CTNNB1 rs3864004 G/G genotype was higher in FA patients compared with the levels in the control group however, the A allele frequency was found lower (p:0.049). EGFR rs845561 gene variant showed no statistically significant difference between FA and control groups (p>0.05). EGFR T allele frequency was detected higher in FA patients who develop OSCC (p:0.03). The EGFR rs845561, and CTNNB1 rs3864004 gene variants may be suggested to contribute to the development of OSCC however, further studies are required.