Summary Introduction: Bone pain from multifocal blastic or mixed lytic-blastic metastatic lesions can be effectively addressed with radiopharmaceuticals with high affinity for such foci. 153Sm-ethylene diamine tetramethylene phosphonic acid (153Sm-EDTMP) and 177Lu-ethylene diamine tetramethylene phosphonic acid) (177Lu-EDTMP) are two such radiopharmaceuticals. The aim of this study was to make a comparison of efficacy between 153Sm-EDTMP and 177Lu-EDTMP in terms of palliation of commonly encountered symptoms in cancer patients, functional status, and pain intensity as measured by Edmonton Symptom Assessment System (ESAS), Eastern Cooperative Oncology Group (ECOG) performance status, and numeric rating scale (NRS) respectively. This study was a double blind randomized clinical trial conducted in a setting of three university hospitals. Materials and Methods: In a randomized double-blind clinical trial 50 patients will with documented painful bone metastases of blastic or mixed lytic-blastic nature were randomly allocated into two groups; group receiving 153Sm-EDTMP and group receiving 177Lu-EDTMP. Radiopharmaceuticals were given at a dose of 37.0 MBq / kg body weight in both groups. Scores on ESAS, ECOG performance status and NRS were recorded before the intervention and following the intervention at 2, 4, 6, and 12 weeks. Hematologic toxicity was evaluated by monitoring hematologic parameters at the baseline and at 1, 3, 6, and 8 weeks after the intervention.Results: Fifty patients, 31 (62 %) females and 19 (38 %) males with the mean age of 66.08 ± 4.53 years were recruited. The baseline means and standard deviations for pain intensity as measured by the NRS were 8.4 ± 1.47 and 8.36 ± 1.43 in 153Sm-EDTMP- and 177Lu-EDTMP-treated subjects respectively. Patients of both groups showed significant alleviation of pain observed from the 2nd week (first follow up session) and continuing to the 12th week after treatment . No difference in response to the two radiopharmaceuticals were seen regarding their efficacy in pain alleviation (P < 1.0). Baseline “symptom distress scores” drawn from the ESAS-r in 153Sm-EDTMP- and 177Lu-EDTMP-treated groups were 5.5 ± 2.1 and 5.4 ± 2.1, respectively. The scores significantly improved in both groups with the most marked rate of improvement achieved within the first two weeks after treatment. The scores continued to improve until the 12th week of follow-up (P < 1.0, non-significant [ns]). Functional status as measured by ECOG performance status scores improved in both groups over the follow up period. Baseline scores on ECOG performance status in 153Sm-EDTMP- and 177Lu-EDTMP-treated groups were 2.5 ± 1.3 and 2.5 ± 1.3 (mean ± standard deviation). At 3 months post-treatment scores improved to 1.6 ± 0.6 and 1.6 ± 0.6 respectively (P < 1.0, n.s.). Conclusions: 153Sm-EDTMP and 177Lu-EDTMP are safe and effective radiopharmaceuticals in palliation of cancer pain from multiple skeletal metastases of blastic and mixed lyticblastic nature.