OBJECTIVE:To explore the prognostic value of the postsurgical half-life (HL) of serum alpha-fetoprotein (AFP). BACKGROUND:There is still a paucity of early surrogate indicators of clinical endpoints after liver resection of hepatocellular carcinoma (HCC). METHODS:The analysis was based on cohorts of 225 (exploration set) and 117 (validation set) treatment-naïve HCC patients undergoing curative liver resection. We defined 3 categories of AFP HL: early complete resolution of AFP, normal HL, and prolonged HL if the HL exceeded 7 days. Overall, probabilities of recurrence and survival were estimated and compared across the AFP HL categories. RESULTS:In the exploration cohort, 48 patients (21.3%) achieved early AFP complete resolution, 116 (51.6%) had normal HL, and 61 (27.1%) had prolonged HL. Long AFP HL was significantly associated with early postoperative recurrence (P < 0.001), as was microvascular invasion. Early recurrence within 2 years of resection was observed in 59% of the patients with prolonged AFP HL compared with only 29.3% of those with normal AFP HL (P < 0.001). A log-rank test followed by multivariate Cox analysis identified an independent function of prolonged AFP HL in predicting shorter recurrence-free survival and overall survival time after HCC resection (hazard ratios, 2.81 and 3.58; P < 0.001). When AFP HL analysis was applied to the validation cohort, the association between prolonged AFP HL and survival endpoints (hazard ratio, 11.63 and 16.39; P < 0.001) was confirmed.