The study aimed to investigate the prognostic role of the preoperative carbohydrate antigen 19-9 (CA19-9) level in alpha-fetoprotein (AFP)-negative (AFP < 25 ng/ml) hepatocellular carcinoma (HCC) patients. From December 2004 to December 2013, 750 patients diagnosed with AFP-negative HCC following curative resection were enrolled. Both univariate and multivariate analyses were performed to clarify the prognostic factors for overall survival (OS) and disease-free survival (DFS). The optimal cutoff point for preoperative CA19-9 was 32.6 U/ml, and the value of the area under the curve was 0.640. The 1-, 3-, and 5-year OS rates were 88.4, 72.2, and 57.0%, respectively, for the CA19-9 > 32.6 U/ml group and 97.0, 83.3, and 79.9%, respectively, for the CA19-9 ae<currency> 32.6 U/ml group (P < 0.001). The 1-, 3-, and 5-year DFS rates were 71.8, 47.7, and 34.8%, respectively, for the CA19-9 > 32.6 U/ml group and 80.8, 63.6, and 55.5%, respectively, for the CA19-9 ae<currency> 32.6 U/ml group (P < 0.001). The multivariate analysis showed that CA19-9 > 32.6 U/ml was one of the most significant unfavorable predictors of OS and DFS (P < 0.001 for both). Preoperative CA19-9 > 32.6 U/ml is a predictor of dismal prognosis and can be employed as a prognostic marker for patient selection in AFP-negative HCC management.