The major cause of cancer mortality is the metastatic spread of tumor cells that can occur via multiple routes, including the vascular system and the lymphatic system. In this study, we developed an IgG-like fusion protein molecule [vascular endothelial growth factor (VEGF) receptor 31-immunoglobulin (VEGFR31-Ig)] which could simultaneously bind the angiogenic growth factor VEGF-A and the lymphangiogenic growth factor VEGF-C. Importantly, VEGFR31-Ig exhibited VEGF-A-binding affinity similar to that of VEGFTrap, the most potent VEGF-A binder, and VEGF-C-binding affinity comparable with that of the soluble fusion protein VEGFR3-Ig (sVEGFR3). Pharmacokinetic analysis in mice showed that VEGFR31-Ig had improved pharmacokinetic properties compared with either VEGFTrap or sVEGFR3. In a highly metastatic human hepatocellular carcinoma (HCCLM3) model in severe combined immunodeficient mice, VEGFR31-Ig potently blocked both tumor angiogenesis and lymphangiogenesis, effectively inhibiting primary tumor growth and metastasis to lungs and lymph nodes. In contrast, VEGFTrap only suppressed primary tumor growth and metastasis to lungs by inhibiting tumor angiogenesis, whereas VEGFR3 was only effective in suppressing tumor metastasis to lymph nodes by blocking tumor lymphangiogenesis. Although a combination of VEGFTrap (25 mg/kg twice weekly) and sVEGFR3 (25 mg/kg twice weekly) can achieve the same therapeutic effect as VEGFR31-Ig (25 mg/kg twice weekly) in the HCCLM3 xenograft mouse model, developing two separate receptor-Ig fusion proteins for clinical use as combination therapy is impractical, mainly owing to regulatory hurdles and cost. Taken together, the VEGFR31-Ig fusion protein presented here has been suggested to have great potential for the treatment of metastatic cancer.