Background Evidence regarding percutaneous vertebroplasty (PV) for chronic painful osteoporotic vertebral compression fractures (OVCFs) remains limited. Purpose To compare pain relief, quality of life, and disability between PV and active control (anesthetic infiltration) interventions for chronic OVCF. Materials and Methods This prospective randomized clinical trial was conducted between May 2013 and June 2019 in participants with pain due to OVCF lasting longer than 3 months with bone marrow edema present at MRI. Study participants were randomly assigned to undergo PV (n = 40) or active control intervention (n = 40). The primary outcome was pain severity, assessed with the visual analog scale (VAS) (range, 0-10) during 12 months after treatment. Secondary outcomes included Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) score (range, 0-100) and Roland Morris Disability Questionnaire (RMDQ) score (range, 0-100). Outcomes were analyzed according to a longitudinal multilevel model used to test the difference between groups in change from baseline across follow-up. Results The mean age of the 80 participants (54 women) was 69 years ± 10 (SD) in the PV group and 71 years ± 10 in the active control group. VAS score was 7.6 (95% CI: 7.0, 8.2) in the PV group and 7.3 (95% CI: 6.9, 7.8) in the active control group at baseline (P = .47) and 3.9 (95% CI: 3.1, 4.8) and 5.1 (95% CI: 4.3, 6.0), respectively, at month 12 (P = .045). At month 12, the group difference from baseline was 1.3 (95% CI: 0.1, 2.6; P = .02) for VAS, 5.2 (95% CI: 0.9, 9.4; P = .02) for QUALEFFO, and 7.1 (95% CI: -3.3, 17.5; P = .18) for RMDQ, favoring the PV group. Conclusion In the treatment of pain caused by chronic OVCFs, PV is more effective for pain relief and quality of life improvement than anesthetic injection alone, with similar improvement for disability between the groups. Clinical trial registration no. NCT01963039 © RSNA, 2023 See also the editorial by Beall and De Leacy in this issue.