Objectives: To identify predictive factors associated with limb volume reduction using different decongestive lymphatic therapy (DLT) systems in patients with lymphoedema, over a period of up to 28 days. Methods: A multicountry (Canada, France, Germany, the United Kingdom) prospective cohort study using (DLT): skin care, exercise, compression bandaging, and manual lymphatic drainage for up to 4 weeks. Reduction in limb volume comparing DLT with (1) standard multilayer bandaging with inelastic material, and with (2) multilayer bandaging with Coban2, together with the identification of factors associated with limb volume changes. Results: Out of 264 patients with upper or lower limb lymphedema, 133 used Coban2 and 131 used standard care. Following DLT, mean limb volume reduction was 941 mL using Coban2 compared with 814 mL using standard care. A difference of 127 mL was found (95% confidence interval -275 to 529 mL, p = 0.53). Of the 176 patients with leg swelling, 166 (94.3%) had a limb volume measurement after 28 days and were included in the risk factor analysis. Of these, 132 (79.5%) were female, with overall mean age of 60.1 years (standard deviation = 14.7), with secondary lymphedema in 102/163 (62.6%). Duration of lymphedema was >10 years in 75/161 (46.6%) and 99/166 (59.7%) were International Society of Lymphology late-stage II/III, indicating longstanding and/or a high frequency of patients with advanced stages of lymphedema. Ninety-one (54.8%) received Coban2 and 75 (45.2%) had standard care. Multivariable factors for a greater leg volume reduction were large initial leg volume (p < 0.001), DLT treatment duration of 4 weeks compared with 2 weeks (p = 0.01), and peripheral arterial disease (p = 0.015). Conclusion: Limb volume changes were found to be similar between groups. Lack of standardization of DLT makes interpretation of effectiveness problematic. There is an urgent need for randomized-controlled trials. Despite this, severe lymphedema with a large limb volume responded well to DLT in this study.