Multivariate analysis showed that mild hypersplenism (HR = 2.063, 95% CI: 1.351–3.151, P < 0.001), severe hypersplenism (HR = 3.754, 95% CI: 2.241–6.287, P < 0.001), positive HBV-DNA copies (HR = 1.571, 95% CI: 1.073–2.300, P = 0.020), serum AFP levels of >400 ƞg/ml (HR = 1.950, 95% CI: 1.335–2.848, P < 0.001), and tumor size of >5 cm (HR = 2.215, 95% CI: 1.482–3.310, P < 0.001) were important independent prognostic factors for OS in patients with HBV-related HCC. The gene discussed is AFP; the disease is hypersplenism.