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Background and Objective: In patients with hepatocellular carcinoma (HCC) receiving potentially curative minimally invasive therapy, autologous cytokine-induced killer (CIK) cells were used to reduce recurrence. In this study we observed the changes in serum alpha-fetoprotein (AFP) after the treatment with CIK cells to explore if AFP could serve as a marker for predicting immunotherapeutic clinical outcome. Methods: A total of 122 patients with HCC and elevated AFP (> 25 ng/mL) 收稿日期: a curative treatment of transcatheter arterial chemoembolization (TACE) plus radiofrequency ablation (RFA) at the Sun Yat-sen University Cancer Center. Of these patients, 83 patients without residual tumor or extrahepatic metastasis and with AFP level less than 1.5 times the normal range (AFP < 37.5 ng/mL) were randomly assigned to the study group (n = 42) and the control group (n = 41). In the study group, CIK cells were transfused intravenously or via common hepatic arteries every week for at least 4 times, and the T-lymphocyte subset data before and after CIK cell infusions was examined by flow cytometry. All the two groups of patients were screened by tomography every 2 months to observe tumor recurrence. Serum AFP was collected at baseline and at different time points after treatment in parallel with radiologic response and clinical outcome. Results: Two patients in the control group were lost to follow-up after treatment. After CIK cell infusions, the downtrend of the AFP level was observed in the study group and not in the control group. There was a significant difference in the level of AFP between different time points after CIK infusions in both groups. The 1-year recurrence rate was 7.14 % for the study group and 23.1% for the control group (P = 0.044). In subgroup analysis, for patients with a slightly high level of AFP (25 ng/mL < AFP < 37.5 ng/mL) after curative TACE plus RFA treatment, the 1-year recurrence rate was 28.57% for the study group and 80% for the control group. The time to recurrence in the study group was also longer than that in the control group (mean 10.2 months vs. 6.8 months). After CIK cell infusions, the percent of CD3+CD4+ T cells and CD4+ /CD8+ T cells increased from 28.1 ± 5.9% and 0.9 ± 0.3% to 32.7 ± 3.6% and 1.2 ±0.2% (P < 0.001 and = 0.004, respectively), while the percent of CD3+CD8+ T cells decreased from 32.9 ±8.4% to 28.8 ± 2.2% (P = 0.046). Also the percentage of patients with hepatitis B virus (HBV)-DNA content less than 1 × 103 copies/mL was 73.5% in the study group and 9.1% in the control group. Conclusions: CIK cells transfusion may reduce the level of serum AFP and anti-HBV and decrease the 1-year recurrence rate of patients with HCC after curative TACE plus RFA. Serum AFP decrease after CIK cell treatment may serve as a useful marker for predicting immunotherapy clinical outcome in patients with HCC undergone curative minimally invasive therapy.