Highly differential gene expression that biologically favored enhanced proliferation in lipedema involved the cell-cycle regulation- and proliferation-related genes ZIC1, UGT1A7, GREM1, TRIM67, Bub1, and HOTAIR. Overall, global gene expression data and pathway enrichment analyses showed significant alterations in the molecular signature of lipedema tissue, with a gene expression profile favoring adipose hyperproliferation, fibrosis, and inflammation, which are consistent with key clinical features of lipedema. This evidence concerns the gene HOTAIR and Lipedema.