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OBJECTIVE: Does short-term use of pneumatic compression devices (PCD) and off-the-shelf compression alleviate symptoms and improve quality of life in women with lipedema and secondary lipolymphedema? METHODS: Prospective, randomized controlled, industry-sponsored, proof-in-principle study comparing PCD plus conservative care (PCD+CC) to CC alone (control). Adult females with bilateral lipedema and secondary lymphedema were randomized to PCD+CC or CC. Outcome measures were lower limb and truncal circumferential measurements, bioimpedance, and quality-of-life, symptom, and pain intensity questionnaires. RESULTS: Both groups experienced improvements in leg circumference and bioimpedance with more improvement in the PCD+CC group than the CC group. Pain scores of the SF-36 survey and numerical rating scales were improved in the PCD+CC group. Wong-Baker Faces scores showed trends toward improvement in both groups. CONCLUSIONS: This proof-in-principle study supports conservative management with graduated compression and with or without PCD for improvement in leg circumference, bioimpedance measurements, and pain in patients with lipedema.