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Aim: Alpha‐fetoprotein (AFP) checkup with abdominal ultrasonography for hepatocellular carcinoma (HCC) surveillance remains controversial. We evaluated a serial AFP‐increase and high AFP levels in the prediction of HCC. Methods: At‐risk patients with chronic liver disease underwent HCC surveillance with trimonthly AFP measurement were included and categorized into HCC and non‐HCC groups. Their AFP levels at 12, 9, and 6 months (−6M) before the outcome date were evaluated. Group‐based trajectory analysis and multivariable regression analysis were performed to identify AFP trajectories as risk predictors for HCC. Results: Overall, 2776 patients were included in the HCC (n = 326) and non‐HCC (n = 2450) groups. Serial AFP levels were significantly higher in the HCC than the non‐HCC groups. Trajectory analysis identified AFP‐increase group (11%) increased 24‐fold risks of HCC compared with the AFP‐stable (89%) group. Compared with patients without the AFP‐increase, a serial 3‐month AFP‐increase ≥10% elevated HCC risk by 12.1‐fold (95% CI: 6.5–22.4) in 6 months, and the HCC risks increased 13–60 fold in patients with cirrhosis, hepatitis B, or C receiving antiviral therapy, or AFP levels <20 ng/ml. Combining serial AFP‐increase ≥10% and AFP ≥20 ng/ml at −6M significantly increased 41.7‐fold (95% CI: 13.8–126.2) HCC risks. In patients who underwent biannual AFP checkups, those with both 6‐month AFP‐increase ≥10% and AFP ≥20 ng/ml increased 22.1‐fold (95% CI: 12.52–39.16) HCC risks in 6 months. Most HCCs were detected at an early stage. Conclusions: Serial 3–6‐month AFP‐increase of ≥10% previously and AFP level of ≥20 ng/ml significantly increased HCC risks in 6 months. [ABSTRACT FROM AUTHOR]