Background: Hepatoblastoma is a rare malignancy originating from pluripotent stem cells with unknown etiology. An understanding of the etiology in pediatric hepatoblastoma has been hampered by the unavailability of sufficient patient samples. To date, only a few epidemiological studies with small sample sizes have been performed investigating risk factors for hepatoblastoma. TP53 and pri-miR-34b/c genes are implicated in the tumorigenesis, yet the role of their polymorphisms in hepatoblastoma susceptibility remains unknown. Methods: We conducted a seven-center case–control study to explore the genetic variants predisposing to hepatoblastoma susceptibility. In our study, we genotyped two functional polymorphisms, the TP53 rs1042522 C>G (Arg72Pro) and miR-34b/c rs4938723 T>C, in 313 cases and 1446 controls using the TaqMan method. Results: Single loci analysis showed that neither TP53 rs1042522 C>G, nor miR-34b/c rs4938723 T>C significantly modified hepatoblastoma risk. In the stratification analysis, we identified that the miR-34b/c rs4938723 TC/CC genotypes were associated with a decreased risk in patients with clinical stages III + IV hepatoblastoma (adjusted odds ratio = 0.53, 95% confidence interval = 0.33–0.84, P=0.007] compared to the rs4938723 TT genotype. Subsequent analysis further showed that the combination of TP53 and miR-34b/c variant genotypes had no impact on susceptibility hepatoblastoma. Conclusions: Taken together, TP53 rs1042522 C>G and miR-34b/c rs4938723 T>C may not confer hepatoblastoma susceptibility. These findings may aid in our understanding of the genetic etiology of hepatoblastoma. © 2020 John Wiley & Sons, Ltd.