The aim of this study was to evaluate the hypothesis that the detection of alpha-fetoprotein (AFP) mRNA-expressing cells could be a novel, direct and accurate method for predicting tumor recurrence after living donor liver transplantation (LDLT) in patients with hepatocellular carcinoma (HCC). The test group consisted of 32 patients who underwent LDLT for end-stage liver disease with HCC. Quantitative real-time reverse transcription polymerase chain reaction was used for the detection of AFP mRNA-expressing cells in the peripheral blood. Nine (28.1%) of the 32 patients developed tumor recurrences during the follow-up period (mean, 27.9 months). The test for the presence of AFP mRNA in the peripheral blood was positive either preoperatively or postoperatively in 11 (34.3%) of the 32 patients, and positive preoperatively in three patients (9.4%). Univariate analysis revealed that a positive preoperative test for peripheral blood AFP mRNA, as well as exceeding Milan criteria and microscopic evidence of vascular invasion were significant predictors for the recurrence of HCC (P = 0.002, 0.049, and 0.001, respectively). Multivariate analysis using Cox's proportional hazards model revealed that a positive preoperative test for peripheral blood AFP mRNA was an independent risk factor for the recurrence of HCC. We concluded that the presence of AFP mRNA-expressing cells preoperatively could be a useful predictor of the recurrence of HCC in liver transplant patients.