Chromosome 4q exhibits high frequency of allelic loss in hepatocellular carcinoma (HCC). This study aimed to elucidate the interaction of the frequent aberrant mRNA expression of alpha-fetoprotein (AFP), osteopontin (OPN) and a novel short isoform of annexin A10 (ANXA10S) at 4q in the tumor progression among 294 patients who received surgical resection of unifocal primary HCC. AFP overexpression, OPN overexpression and ANXA10S down-regulation correlated with high-grade and high-stage tumors, early tumor recurrence (all P<0.0001), and lower 10-year survival (all P=0.000001). The AFP overexpression correlated with OPN overexpression (P=0.0026) and ANXA10S down-regulation (P=0.00001), while OPN overexpression correlated with ANXA10S down-regulation (P=0.00001). Pair-wise combinations revealed interactive effects between these genetic variants for tumor grade, tumor stage and early recurrence (all P<0.0001). HCCs with more genetic aberrations had more frequent high tumor grade, portal vein invasion (stage IIIB-IV) and early recurrence (all P<0.0001). The 10-year survival rate for HCCs with all three genetic alterations was the lowest (7%), followed by those with two (22%) or one event (29%), and the highest for those without these changes (43%), P=0.000001. The prognostic stratification using these molecular factors was similar to that of histopathological staging. These three genetic alterations also helped to identify different subgroups of patients of stage II HCC but with different prognosis (P=0.015). In conclusion, the aberrant expressions of AFP, OPN and ANXA10S cooperatively contribute to tumor progression and poor prognosis, and are useful for molecular staging of HCC and the subclassification of stage II HCC without vascular invasion.