We evaluated the influence of the vascular endothelial growth factor (VEGF) -C936T polymorphism on prognosis of hepatocellular carcinoma (HCC), cirrhosis, and hepatitis C virus (HCV) infection. Serum VEGF and alpha-fetoprotein (AFP) levels were determined and used to characterize sensitivity and specificity. A total of 285 subjects were studied: 68 HCC, 118 cirrhosis, 43 HCV, and 56 healthy controls. Prevalence of the VEGF -C936T polymorphism and serum levels of VEGF and AFP were analyzed by polymerase chain reaction-restriction fragment length polymorphism and enzyme-linked immunosorbent assay, respectively. The genotype CC (frequencies between 63.24 and 76.79%; P > 0.05) and the C allele (absolute frequencies from 0.816 to 0.884, P > 0.05) were prevalent in all groups. Higher VEGF levels in HCC patients (588.0 ± 501.0 pg/mL) were observed, particularly in patients with the T allele in VEGF -C936T (764.4 ± 571.7 pg/mL) compared to those in the other groups (P < 0.05). The same trend occurred with AFP levels (HCC = 8.522 ± 23.830; cirrhosis = 12.7 ± 59.3; HCV = 4.6 ± 4.7; control = 2.7 ± 1.8 ng/mL; P = 0.005). Levels of VEGF and AFP showed sensitivity of 65 and 28% and specificity of 85 and 99%, respectively, for HCC patients. In conclusion, the VEGF -C936T polymorphism is not associated with HCC but the mutant allele (T) increases VEGF levels in HCC patients. VEGF could be a potential biomarker for HCC, while AFP could be used to distinguish between patients with HCC and cirrhosis or HCV.