Background <p>Hepatoblastoma (HB) is the most common malignant solid tumor of the liver in children and is a fatal disease with a poor prognosis. Therefore, indicators that can be used for the early prediction of the HB prognosis are necessary. Sodium glucose cotransporter 2 (SGLT2) is a glucose transporter protein present in the proximal renal tubules. Studies have shown that SGLT2 is associated with the occurrence of tumors and is upregulated in various tumors. Peroxiredoxin 4 (PRDX4) is an antioxidant enzyme with a secretory function and is located in the cytoplasmic endoplasmic reticulum. Recent reports have suggested that it is closely related to the development and prognosis of various cancers. To some degree, this is highly suggestive of the interplay between SGLT2 and PRDX4.</p> Methods <p>In the present study, clinical data and post-surgical paraffin-embedded specimens from 75 HB patients were collected, and hematoxylin and eosin and immunohistochemical staining of SGLT2 and PRDX4 were used to analyze their expression and correlation with the clinicopathological features and prognosis.</p> Results <p>We found that low SGLT2 and high PRDX4 expression predicted a significantly shorter survival and worse clinical condition in HB patients. Furthermore, when low SGLT2 expression was combined with high PRDX4 expression, the event-free survival and overall survival were significantly reduced. Univariate and multivariate Cox proportional hazards analyses showed that low SGLT2 and high PRDX4 expression in HB were independent prognostic factors for the survival after surgical resection.</p> Conclusion <p>The immunohistochemical combination of low SGLT2 and high PRDX4 expression can independently predict a poor prognosis in HB patients.</p>