This prospective study compared ¹⁷⁷Lu-ethylene diamine tetramethylene phosphonate (EDTMP) with ¹⁵³Sm-EDTMP for painful skeletal metastases. Methods: Half of the 32 patients were treated with 177Lu- EDTMP and half with ¹⁵³Sm-EDTMP, at 37 MBq/kg of body weight. Analgesic, pain, and quality-of-life scores (EORTC, Karnofsky, ECOG) and bone proliferation marker were used to examine efficacy. Hematologic toxicity was evaluated using NCI-CTCAE and compared between groups at baseline and each month till 3 mo after therapy. Pain relief was categorized as complete, partial, minimal, or none. Results: Pain relief with ¹⁷⁷Lu-EDTMP was 80%: 50% complete, 41.67% partial, and 8.33% minimal. Pain relief with ¹⁵³Sm-EDTMP was 75%: 33.33% complete, 58.33% partial, and 8.33% minimal. The difference was not significant (P = 1.000). Quality of life at 3 mo after therapy improved significantly in both groups as per ECOG score (P = 0.014 and 0.005 for ¹⁷⁷Lu-EDTMP and ¹⁵³Sm-EDTMP, respectively), Karnofsky index (P = 0.007 and 0.023 for ¹⁷⁷Lu- EDTMP and ¹⁵³Sm-EDTMP, respectively), and EORTC score (P = 0.004 and , 0.001 for ¹⁷⁷Lu-EDTMP and ¹⁵³Sm-EDTMP, respectively). Bone proliferation marker in responders of both groups dropped significantly (P = 0.008 for ¹⁷⁷Lu-EDTMP and P = 0.019 for ¹⁵³Sm-EDTMP), parallel to clinical response. For ¹⁷⁷Lu-EDTMP, anemia, leukopenia, and thrombocytopenia were nonserious (grade I/II) in 46.67%, 46.67%, and 20%, respectively,  and serious (grade III/IV) in 20%, 6.67%, and 0%, respectively. For ¹⁵³Sm-EDTMP, anemia, leukopenia, and thrombocytopenia were nonserious (grade I/II) in 62.5%, 31.25%, and 18.75%, respectively, and serious (grade III/IV) in 18.75%, 0%, and 6.25%, respectively. One patient treated with ¹⁵³Sm-EDTMP had grade IV thrombocytopenia but required no blood transfusion. Differences between groups were not significant for either nonserious or serious toxicity. For ¹⁷⁷Lu-EDTMP, 3 of 12 responders experienced the flare phenomenon on the third day after therapy and one on the fifth day, showing no response to therapy. For ¹⁵³Sm- EDTMP, 2 of 12 responders experienced the flare phenomenon, both on the third day after therapy. Conclusion: ¹⁷⁷Lu-EDTMP has pain response efficacy similar to that of ¹⁵³Sm-EDTMP and is a feasible and safe alternative, especially in centers with no nearby access to ¹⁵³Sm-EDTMP.