alpha-fetoprotein (AFP) messenger RNA (mRNA) has been proposed as a marker of hepatocellular carcinoma (HCC) cells disseminated into the circulation, but its clinical significance remains controversial. We prospectively assessed the prognostic value of AFP mRNA in patients undergoing curative hepatic resection for HCC. Peripheral blood samples were taken from 87 patients before and after surgery to determine the presence of AFP mRNA by use of a reverse-transcription polymerase chain reaction. A primary endpoint was recurrence-free interval. AFP mRNA was detectable preoperatively in 31 patients (36%) and postoperatively in 30 patients (34%). With a median follow-up period of 28 months (range, 3-41 months), HCC recurred in 46 patients (53%). Among 4 groups separated according to preoperative and postoperative AFP mRNA status, patients with consistent positivity of AFP mRNA showed the highest recurrence rate (85%) and trend to distant or multiple recurrence. The recurrence-free interval was significantly shorter in patients with postoperative positivity of AFP mRNA than in those without (53% [95% CI, 36-71] vs. 88% [95% CI, 79-96] at 1 year, 37% [95% CI, 17-57] vs. 60% [95% CI, 46-75] at 2 years; P =.014), whereas the preoperative positivity of AFP mRNA provided no significance (P =.100). Cox's proportional-hazards model identified the postoperative positivity of AFP mRNA as an independent prognostic factor for HCC recurrence (relative risk, 2.33; 95% CI, 1.26-4.34; P =.007). In conclusion, postsurgical recurrence of HCC can be predicted by detecting AFP mRNA-expressing cells in peripheral blood.