Serum levels of carbohydrate antigen 19-9 (CA 19-9) were shown to be associated with poorer prognosis in several cancers, but the prognostic role of CA 19-9 levels in patients with hepatocellular carcinoma was unclear. A retrospective cohort of 97 patients with resectable hepatocellular carcinoma was performed to assess the prognostic role of CA 19-9 levels on overall survival in hepatocellular carcinoma. Both Kaplan-Meier product-limit method and multivariate analysis were performed to determine the prognostic role of CA 19-9 levels. The results indicated that among those 97 patients, 24 (24.7%) had elevated preoperative CA 19-9 levels (≥37 U/mL). Elevated serum CA 19-9 levels did not correlate with patient age, gender, tumor size, tumor stage, diabetes, and hepatitis B virus (HBV) infection. Kaplan-Meier product-limit method showed that patients with elevated CA 19-9 levels had poorer survival than those with normal CA 19-9 levels (log-rank test P < 0.001). Multivariate analysis showed that elevated CA 19-9 level was a significantly independent predictor of poorer overall survival (hazard ratio [HR] = 2.56; 95% confidence interval [95% CI] 1.41-4.64, P = 0.002). In addition, tumor stages and multiple tumors were also independent predictors of poorer overall survival in hepatocellular carcinoma (P < 0.01). In conclusion, serum CA 19-9 levels have an independent prognostic role in patients with resectable hepatocellular carcinoma. Elevated CA 19-9 level is significantly associated with poorer overall survival in hepatocellular carcinoma.