Introduction: Targeted radionuclide therapy (TRT) has been demonstrated to be an effective therapeutic tool in patients with disseminated bone metastasis. TRT is generally performed with a single radionuclide. In this study we investigated the feasibility of combined TRT with a high-energy beta emitter (Sm-153) and a low energy beta emitter (Lu-177) in wistar rats. Methods: The cocktail complex of Sm-153/Lu-177-EDTMP was prepared. To determine the effect of metal-to-ligand (Me:EDTMP) molar ratio on labeling yield, several complex were analyzed after changing Me:EDTMP molar ratio from 1:1 to 1:50. Sm-153/Lu-177-EDTMP was administered intravenously through the tail vein of wistar rats. Biodistribution data were collected at 2 hours to 7 day post injection and scintigraphic images were taken at 24 hours and 1, 2 week after administration of radiopharmaceutical. Results: The results revealed high skeletal uptake (3.5% and 3.4% ID/g at 24 hours post injection for Sm-153 and Lu-177, respectively) with rapid blood clearance and minimal uptake in any of the major organs. Scintigraphic images verified high skeletal uptake. Conclusion: Our results indicate that the combination of Sm-153 and Lu-177 is feasible and safe. This study suggests that the combination of different radionuclides with different radiation energies and half-life, such as Sm-153 and Lu-177, could be advantageous in patients with tumoral lesions of different sizes.