<h4>Background</h4>Secondary lymphedema is a common complication of cancer treatment and epidermal changes are recognised as histological hallmarks of secondary lymphedema; however, the role of keratinocytes in the pathophysiology of this disease remains unclear.<h4>Methods</h4>Hyperkeratosis, up-regulation of protease-activated receptor 2 (PAR2) and Th2-inducing cytokines were assessed in biopsy specimens from patients with unilateral breast cancer-related lymphedema (BCRL) and in a mouse model of lymphedema. This evidence concerns the gene F2RL1 and Hyperkeratosis.