Recent advances in technology have allowed intermittent pneumatic compression (IPC) devices to develop so that their function mimics the process and principles of manual lymphatic drainage (MLD); however, research into the effectiveness of such devices is lacking. This study aimed to investigate the effectiveness of a patented IPC technique designed to mimic MLD (the LymphAssist), compared with a typical sequential IPC regimen. Forty patients with a confirmed diagnosis of lower limb ISL (International Society of Lymphology) stage II or III lymphedema were recruited into this three-phased study. A bilateral leg volume assessment and quality-of-life assessment were completed at four clinic visits across the course of the study. The LymphAssist IPC regimen was significantly more effective in reducing distal leg volume than the sequential mode (mean volume reduction: 230 ± 135 mL vs. 140 ± 84 mL, respectively,  = 0.01). Improvements in leg volume were transient as both groups demonstrated a rebound or increase in volume during the washout period (LymphAssist: 238 ± 168 mL, sequential: 276 ± 158 mL,  = 0.3). Overall, IPC was effective in improving quality-of-life scores (mean reduction: 10 ± 11,  < 0.001). IPC is effective in reducing limb volume and improving quality of life for patients with lower limb lymphedema. IPC that mimics the MLD process has been shown to be more effective in reducing leg volume compared with traditional sequential IPC in the distal aspect of the leg. The increase in leg volume observed after discontinuation of IPC suggests that regular treatment is required to maintain its associated effects. Clinical Trial Registration Number: NTC 03856281.