Clinicians often experience extrahepatic metastases associated with hepatocellular carcinoma (HCC), even if no evidence of intrahepatic recurrence after treatment is observed.We investigated the pretreatment predictors of extrahepatic metastases in HCC patients.Patients diagnosed with HCC without evidence ofextrahepatic metastases were prospectively enrolled.We evaluated the correlation between extrahepatic metastases and pretreatment clinical variables, including serum tumor markers.A total of 354 patients were included.Seventy-six patients (21%) had extrahepatic metastases during the observation period (median, 25.3 months;range, 0.6-51.3 months).Cox regression multivariate analysis showed that serum protein induced by vitamin K absence or antagonist-Ⅱ (PIVKA-Ⅱ) production levels, the intrahepatic tumor stage, platelet count, and portal vein thrombosis were independent risk factors for extrahepatic metastases.Patients with a PIVKAⅡ production ≥'3d 300 mAU/mL had a 2.7-fold (95% confidence interval;1.5-4,8;P < 0.001) and 3.7-fold (95%confidence interval;2.0-6.6;P < 0.001) increased risk for extrahepatic metastases after adjustment for stage, platelet count, alpha-fetoprotein ≥'3d 400 ng/mL, and portal vein thrombosis according to the AJCC and BCLC staging systems,respectively.When we analyzed the subgroups with all variables included at the time of diagnosis according to the AJCC tumor stage, the serum PIKVA-Ⅱ (P < 0.001) and platelet count (P =0.022) in stage Ⅰ, serum AFP (P =0.018)and PIVKA-Ⅱ (P =0.008) in stage Ⅱ, and serum PIVKA-Ⅱ (P =0.023) and platelet count (P =0.031) in stage Ⅲ were risk factors for extrahepatic metastases in univariate analysis.In multivariate analysis, only the serum PIVKAⅡ level was an independent predictive factor of extrahepatic metastases in patients with stage Ⅰ (P =0.001), Ⅱ (P =0.023), and Ⅲ (P =0.028) disease.In particular, a serum PIVKA-Ⅱ level ≥'3d 300 mAU/mL had a 8.8-fold (95% CI,2.538-30.303, P < 0.001), 3.4-fold (95% CI, 1.179-9.523, P =0.025), and 2.2-fold (95% CI, 1.086-4.504, P =0.025)increased risk among patients with stages Ⅰ, Ⅱ, and Ⅲ disease compared to patients with serum PIVKA-Ⅱ levels <300 mAU/mL in multivariate analysis after adjustment for AFP ≥'3d 400, PT, and platelet count.PIVKA-Ⅱ production levels might be a good candidate predictive marker for extrahepatic HCC metastases, especially in patients with smaller and/or fewer tumors in the liver with in stages regardless of serum alpha-fetoprotein.