Background: Osteolytic lesions are present in 75% of patients with multiple myeloma (MM) and frequently require palliation with radiation therapy (RT). Prior case series of patients with MM with bone pain undergoing palliative RT suggests doses ≥12 Gy (equivalent dose in 2Gy fractions, EQD2) provide excellent bone pain relief. However, recent advances in care and novel biologic agents have significantly improved overall survival and quality of life for patients with MM. We hypothesized that lower-dose RT (LDRT, EQD2 <12 Gy) offers an effective alternative to higher-dose RT (HDRT, EQD2 ≥12 Gy) for palliation of painful, uncomplicated MM bone lesions. Methods: We retrospectively identified patients with MM treated with RT for uncomplicated, painful bone lesions and stratified by EQD2 ≥/< 12 Gy. Clinical pain response (CPR) rates, acute and late toxicity, pain response duration, and retreatment rates between LDRT and HDRT groups were analyzed. Results: Thirty-five patients with 70 treated lesions were included: 24 patients (48 lesions) treated with HDRT and 11 patients (22 lesions) with LDRT. Median follow-up was 14 and 16.89 months for HDRT and LDRT, respectively. The median dose of HDRT treatment was 20 Gy versus 4 Gy in the LDRT group. The CPR rate was 98% for HDRT and 95% for LDRT. There was no significant difference in any-grade acute toxicity between the HDRT and LDRT cohorts (24.5% vs 9.1%, Χ2 P = .20). Pain recurred in 10% of lesions (12% HDRT vs 9.5% LDRT). Median duration of pain response did not significantly differ between cohorts (P = .91). Five lesions were retreated, 2 (9.5%) in the LDRT cohort, and 3 (6.3%) in the HDRT cohort. Conclusion: In this study, LDRT effectively palliated painful, uncomplicated MM bony lesions with acceptable CPR and duration of palliation. These data support prospective comparisons of LDRT versus HDRT for palliation of painful, uncomplicated MM bony lesions.