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Lymphedema is a common and debilitating complication following cancer treatment with surgical lymph node excision and radiotherapy. Currently there are no curative treatments for lymphedema. Animal models that intended to replicate the disease have been inadequate, making a troublesome transition from experimental therapeutic studies into the clinic. It is therefore imperative to establish an experimental animal model that can reliably replicate clinical lymphedema.To discover the optimal method of lymphedema induction, surgical lymph ablation and irradiation or silicone splint emplacement were combined in 8 experimental groups (n = 4). In total, 32 mice served in this study and were followed for 8 weeks after surgery. Outcomes included micro–computed tomography hind limb volumetry, lymphatic clearance measured with technetium Tc 99m (99mTc) human serum albumin lymphoscintigraphy and lymph vessel ectasia quantified with LYVE-1 immunohistochemistry.All trialed models but one resulted in only transient lymphedema or lasting lymphedema with adverse morbidity. Combined surgical lymph obstruction with 2 fractions of 10-Gy irradiation successfully induced lasting lymphedema without adverse events. Over the 8 weeks' follow-up, limb volumes were significantly increased at all time points (P < 0.001), lymph drainage was impaired (P < 0.001), and lymph vessels were ectatic (P < 0.001), when compared with the unoperated limbs.The presented model of acquired lymphedema is a reduction and refinement of previous works and can transpose to future observational and interventional studies. In addition, it is shown how 99mTc-HSA lymphoscintigraphy can quantify lymphatic clearance, which can prove insightful in therapeutic studies aiming to enhance lymphatic drainage.