Objective To identify the changes of serum alpha-fetoprotein (AFP) and AFP-L3 levels after surgical resection of hepatocellular carcinoma (HCC), so as to evaluate the role of AFP-L3 in predicting post-operative HCC recurrence. Methods A total of 67 HCC patients who received surgical resection from Jan. 2007 to Dec. 2007 were enrolled in the present study. The detailed clinical data were obtained for each patient. Pre- and post-operative serum AFP and AFP-L3 levels were measured continuously, and patterns of their post-operative changes were followed up for a long-term period. Results The overall 1-, 2- and 3-year recurrence rates of the patients were 23.9%(16/67), 38.8%(26/67) and 50.7%(34/67), respectively. There was no relationship between serum AFP and AFP-L3 level before operation (r_s=0.176, P=0.155). The pre-operation serum AFP-L3 level was significantly correlated with tumor recurrence (r_s=0.327, P=0.007), but the relation between pre-operation serum AFP level and tumor recurrence was not clear yet(r_s=0.240, P=0.051). Conclusion Serum AFP-L3 level is associated with HCC recurrence and therefore valuable for predicting HCC recurrence; it can provide clinicians with more information for judging the therapeutic efficacy of HCC patients.