Importance: Bone accrual during youth is critical to establish sufficient strength for lifelong skeletal health. Children with cancer may develop low bone mineral density (BMD) any time before or after diagnosis. Objective: To evaluate the ability of low-magnitude, high-frequency mechanical stimulation to enhance BMD among childhood cancer survivors. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at St Jude Children's Research Hospital from June 1, 2010, to January 22, 2013, using cancer survivors, ages 7 to 17 years, who were previously treated at St Jude Children's Research Hospital, were in remission, and at least 5 years from diagnosis, with whole-body or lumbar spine BMD z scores of -1.0 or lower. Participants were randomized (stratified by sex and Tanner stage) to either a placebo device or low-magnitude, high-frequency mechanical stimulation device, which was used at home. Interventions: Placebo or low-magnitude, high-frequency mechanical stimulation (0.3 g; 32-37 Hz) for 2 sessions lasting 10 minutes each, 7 days per week for 1 year. All participants were prescribed daily cholecalciferol (vitamin D) and calcium. Main Outcomes and Measures: Changes in areal and volumetric BMD and bone biomarkers were compared by analysis of variance, adjusted for strata. Results: Of the 65 participants, 32 were randomized to the intervention group (mean [SD] age was 13.6 [3.7] years, 18 [56.2%] were male, and 27 [84.4%] were white), and 33 were randomized to the placebo group (mean [SD] age was 13.6 [2.9] years, 17 [51.5%] were male, and 26 [78.8%] were white). Forty-eight participants completed the trial, 22 in the intervention group and 26 in the placebo group with median adherence of 70.1%for intervention and 63.7%for placebo groups. With intention-to-treat analysis, mean (SD) whole-body BMD z score by dual x-ray absorptiometry improved by 0.25 (0.78) in the intervention (n = 22), but decreased by -0.19 (0.79) in the placebo group (n = 26, P = .05). Circulating osteocalcin at 12 months correlated with change in total body BMD (r = 0.35, P = .02). Tibial trabecular bone among participants completing 70% or more of the prescribed sessions increased by a mean of 11.2%(95%CI, 5.2 to 17.2%) compared with those completing less than 70%who decreased by a mean of -1.3%(95%CI, -7.3 to 4.7%; P = .02). Change in circulating receptor activator of nuclear factor κ-B ligand was higher in the intervention than in the placebo group (0.06 [0.16] vs -0.04 [0.17] pmol/L) (P = .04). Conclusions and Relevance: Pediatric cancer survivors with low BMD may benefit from low-magnitude, high-frequency mechanical stimulation as a novel and safe intervention to optimize peak bone mass during youth, alone or in conjunction with other therapies.