Hepatocellular carcinoma (HCC) constitutes a challenging health problem in Egypt due to the high incidence of hepatitis C virus (HCV) infection. Improved understanding of genetic mechanisms underlying the individual predisposition to HCC will lead to enhancements in the early diagnosis, treatment, and prevention of this disease. Transcription factor forkhead box P1 (FOXP1) is involved in the cellular processes of proliferation, differentiation, metabolism, and longevity. In addition, it has been implicated in hepatic tumorigenesis. The present study explored the association of C/A single-nucleotide polymorphism in the FOXP1 gene (rs2687201) with HCC susceptibility in HCV Egyptian patients. The study included 108 patients with HCV-dependant HCC, 86 HCV patients, and 80- age and gender-matched healthy controls. rs2687201 genotyping was performed by allelic discrimination method using TaqMan real-time PCR assays while FOXP1 gene expression and protein level were determined using qRT-PCR and enzyme-linked immunoassay, respectively. Our results revealed a significant association between FOXP1 rs2687201 and HCC risk where (A) allele was significantly more frequent in patients with HCC compared to controls (odds ratio [OR]: 1.88, 95% confidence interval [CI]: 1.17–3.04, p = 0.01) and to HCV patients (OR: 1.85, 95% CI: 1.62–2.94, p = 0.012). Furthermore, FOXP1 gene and protein expression levels were remarkably higher in (CA + AA) than in CC genotype carriers in a dominant model. The (CA + AA) genotype displayed a significantly shorter overall survival than the CC genotype in HCC patients. In conclusion, FOXP1 gene polymorphism rs2687201 is significantly associated with HCC, but not with HCV infection, in Egyptian patients.