Background and Aims Liver transplantation has become increasingly crucial in treating liver cancer. However, the clinical issue of tumor recurrence and metastasis after transplantation remains unresolved. This study aimed to analyze the relationship between interleukin 34 (IL-34) expression and the prognosis, tumor recurrence, and metastasis in liver cancer transplant recipients. It also aimed to explore its role in the growth and metastasis of liver cancer.Methods The expression of preoperative serum IL-34 of 93 liver cancer transplant recipients was detected using the ELISA method. Statistical methods were used to analyze the relationship between IL-34 expression and clinicopathologic characteristics and prognosis. The diagnostic value of IL-34 in detecting tumor recurrence and metastasis was analyzed using the receiver operating characteristic (ROC) curve. Human hepatocellular carcinoma orthotopic xenograft models were established in male 5-6-week-old NOD/SCID mice, which were randomly divided into four groups and intraperitoneally injected with different concentrations of IL-34 (5, 10, 35 μg/kg) or an equal amount of saline (control group) once daily for a total of two weeks. After ten weeks, the overall survival rate, tumor volume and mass, and lung tissue metastasis of the mice in each group were compared. Western blot was used to detect the expression of cell proliferation-related proteins (Ki-67 and PCNA), tumor metastasis-related proteins (MMP-2 and MMP-9), and epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, vimentin, and snail) in the transplanted tumors of each group.Results After a 5-year follow-up, among the 93 liver cancer transplant recipients, 27 cases experienced tumor recurrence, 9 cases experienced metastasis, and 45 cases died. The expression levels of IL-34 in patients with tumor recurrence or metastasis were significantly lower than those without tumor recurrence or metastasis (both P<0.05). Low expression of IL-34 was negatively correlated with tumor recurrence, metastasis, and vascular invasion (all P<0.05). The 5-year overall survival rate and tumor-free survival rate of patients with low IL-34 expression were significantly lower than those with high IL-34 expression (both P<0.05). Low expression of IL-34 and tumor recurrence and metastasis were independent risk factors for overall survival (all P<0.05). The area under the curve (AUC) for serum IL-34 in detecting tumor recurrence and metastasis was 0.93 and 0.79, respectively, superior to AFP. Compared with the control group, the overall survival rate of mice in the three IL-34 intervention groups increased, tumor volume and weight decreased, lung tissue metastasis rate and number of metastatic lesions decreased, and the expression levels of Ki-67, PCNA, MMP-2, MMP-9, vimentin, and snail proteins in the transplanted tumors decreased. In contrast, the expression level of E-cadherin increased, all of which showed a concentration-dependent relationship (all P<0.05).Conclusion Low expression of serum IL-34 is closely associated with adverse prognosis, tumor recurrence, and metastasis in liver cancer transplant recipients. IL-34 inhibits the growth and metastasis of liver cancer, possibly through the inhibition of cell proliferation and EMT.