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OBJECTIVE: Advanced pneumatic compression devices (APCDs) have been shown to be an effective intervention for lymphedema when used as part of a self-care maintenance treatment regimen. However, adherence to self-care is poor, and APCDs require patients to be immobile during treatment. We sought to evaluate the safety and efficacy of a novel non-pneumatic compression device (NPCD) for treating lymphedema versus an APCD. METHODS: A randomized, crossover head-to-head investigation at five US sites in 2021. Patients were randomized to either the NPCD or a commercially-available APCD. Subjects used the randomly assigned initial device for 28 days with a 4-week washout period prior to a comparable 28-day utilization of the second device. RESULTS: Data from 50 adult women with unilateral breast cancer-related lymphedema (BCRL) were analyzed. When compared with the APCD, the NPCD was associated with greater mean reduction in limb edema volume (64.6% vs. 27.7%, p<0.001), significantly greater mean improvements in quality of life scores, greater adherence (95.6% vs. 49.8%, p<0.001), and greater satisfaction with the device (90% vs. 14%, p<0.001). Patients indicated that the NPCD facilitated exercise and was convenient for travel. No adverse events were reported. CONCLUSIONS: The novel NPCD is an effective maintenance treatment for reducing limb volume in BCRL patients. The device was more effective than an APCD and resulted in higher adherence to self-care interventions and greater patient satisfaction.