Objective The aim of the study was to determine the risk factors affecting postoperative survival in patients with alpha-fetoprotein (AFP) negative (AFP <20 ng/ml) hepatocellular carcinoma (HCC). Methods A total of 479 patients with HCC who underwent radical resection were included in this study. Independent prognostic factors for AFP-negative HCC patients were determined using univariate and multifactorial cox regression analysis. the Kaplan-Meier method was used to assess the probability of survival, and log-rank tests were performed. Result: Age (HR=1.047, 95% CI: 1.002-1.094), CEA (HR=1.151, 95% CI: 1.027-1.290), CA19-9 (HR=1.053, 95% CI: 1.002-1.105), AST (HR=1.031, 95% CI: 1,001-1.070) and tumor size (HR=1.289, 95% CI: 1,161-1.432) were independent risk factors for survival in AFP-negative HCC patients. Elevated values of the 5 risk factors had a negative impact on prognosis and were independent risk factors for overall survival (OS) (P<0.05). OS was higher in AFP-negative HCC patients than in AFP-positive HCC patients (P<0.001). Conclusion AFP-negative patients undergoing surgical treatment for HCC require attention to liver function and tumor indexes, especially in patients older than 65 years and with tumor size greater than 6 cm.