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Lymphedema is a chronic, progressive, and incurable condition that leads to lymphatic fluid retention; it may be primary (heritable) or secondary (acquired) in nature. Although there is a growing understanding of lymphedema, methods for the prevention and treatment of lymphedema are still limited. In this study, we investigated differential protein expressions in sham\u2010operated and lymphedema\u2010operated mice for 3\u2009days, using two\u2010dimensional gel electrophoresis (2\u2010DE) and mass spectrometry analysis. Male improved methodology for culturing noninbred (ICR) mice developed lymphedema in the right hindlimb. Twenty functional proteins were found to be differentially expressed between lymphedema induced\u2010right leg tissue and normal left leg tissue. Out of these proteins, the protein levels of apolipoprotein A\u20101 preprotein, alpha\u2010actinin\u20103, mCG21744, parkinson disease, serum amyloid P\u2010component precursor, annexin A8, mKIAA0098 protein, and fibrinogen beta chain precursor were differentially upregulated in the lymphedema mice compared with the sham\u2010operated group. Western blotting analysis was used to validate the proteomics results. Our results showing differential up\u2010regulation of serum amyloid P\u2010component precursor, parkinson disease, and apolipoprotein A\u20101 preprotein in lymphedema model over sham\u2010operated model suggest important insights into pathophysiological target for lymphedema. 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