BACKGROUND & OBJECTIVE Alpha-fetoprotein (AFP) is a marker often used to detect carcinoma cells in peripheral blood of patients with hepatocellular carcinoma (HCC). This study was to explore the correlation of perioperative AFP expression in peripheral blood to recurrence of HCC. METHODS Peripheral blood samples from 56 HCC patients, obtained perioperatively, were tested for the presence of AFP mRNA by nested reverse transcription-polymerase chain reaction (RT-PCR) and TaqMan MGB probe real-time quantitative PCR. The peripheral blood samples from 15 patients with benign liver masses and cirrhosis, and 30 healthy volunteers were used as control. RESULTS The positive rate of AFP mRNA in preoperative peripheral blood was significantly higher in HCC patients than in patients with benign liver masses and cirrhosis (42.9% vs. 13.3%, P=0.035) and healthy volunteers (42.9% vs. 10.0%,P=0.002). The expression of AFP mRNA in preoperative peripheral blood was significantly related to tumor vascular invasion, either observed macroscopically (P=0.029) or microscopically (P<0.001). The 1-, 2-, and 3-year overall and disease-free survival rates were significantly higher in AFP-negative patients than in AFP-positive patients (P=0.003, P=0.039). Cox multivariate analysis showed that preoperative expression of AFP mRNA in peripheral blood was an independent factor for predicting recurrence (P=0.018). The positive rate of AFP mRNA in postoperative peripheral blood samples from HCC patients was 37.5%. The presence of AFP mRNA in postoperative peripheral blood was not related to any clinicopathologic factors, AFP mRNA levels in preoperative peripheral blood, and prognosis of the HCC patients. CONCLUSION The presence of AFP mRNA in preoperative peripheral blood is related to tumor invasion of HCC, and may be a predictor maker of tumor recurrence.