Background <p>Lutetium-177 (¹⁷⁷Lu) is a promising radionuclide for targeted cancer therapy due to its favorable theranostic properties. Transarterial lipiodol embolization is widely used for hepatocellular carcinoma (HCC), but the potential of ¹⁷⁷Lu emulsified into lipiodol (¹⁷⁷Lu-lipiodol) remains underexplored. This study aimed to evaluate the partition coefficient, biodistribution, and antitumor efficacy of ¹⁷⁷Lu-lipiodol in a preclinical xenograft model.</p> Methods <p>After synthesizing ¹⁷⁷Lu-oxine from ¹⁷⁷Lu-chloride, the product was emulsified in lipiodol. Its radiochemical purity and partition coefficient were measured. F344 NJcl rnu/nu rats (n = 5) bearing bilateral thigh tumors (HC-4 cells) were randomized to receive ¹⁷⁷Lu-lipiodol (2.8&#xa0;MBq in 50 μL) or non-labeled lipiodol (50 μL) via surgical exposure and direct puncture of the right femoral artery. SPECT/CT images were acquired over 14&#xa0;days, and biodistribution was confirmed by gamma counting at day 28. Tumor volumes and body weights were monitored to assess treatment response and toxicity.</p> Results <p>The ¹⁷⁷Lu-lipiodol emulsion was obtained with a high radiochemical purity (&gt; 99%). SPECT/CT showed high tumor accumulation (34.0% ± 4.4% immediately post-injection) that persisted up to day 28 (7.3% ± 1.2% of injected dose). Tumor growth was significantly suppressed with a treated-to-untreated volume ratio of 0.45 at day 14 (p = 0.017) and 0.59 at day 21 (p = 0.001). While off-target uptake was limited, moderate splenic accumulation (26.6% ± 17.5% ID) was noted. No marked body weight changes or gross organ abnormalities were observed.</p> Conclusion <p>¹⁷⁷Lu-lipiodol for HCC therapy demonstrated effective tumor targeting and growth suppression of HCC in a preclinical xenograft model.</p>