Lipedema is an adipose tissue disorder characterized by the disproportionate increase of subcutaneous fat tissue in the lower and/or upper extremities. The underlying pathomechanism remains unclear and no molecular biomarkers to distinguish the disease exist, leading to a large number of undiagnosed and misdiagnosed patients. To unravel the distinct molecular characteristic of lipedema we performed lipidomic analysis of the adipose tissue and serum of lipedema versus anatomically- and body mass index (BMI)-matched control patients. Both tissue groups showed no significant changes regarding lipid composition. As hyperplastic adipose tissue represents low-grade inflammation, the potential systemic effects on circulating cytokines were evaluated in lipedema and control patients using the Multiplex immunoassay system. Interestingly, increased systemic levels of interleukin 11 (p = 0.03), interleukin 28A (p = 0.04) and interleukin 29 (p = 0.04) were observed. As cytokines can influence metabolic activity, the metabolic phenotype of the stromal vascular fraction was examined, revealing significantly increased mitochondrial respiration in lipedema. In conclusion, despite sharing a comparable lipid profile with healthy adipose tissue, lipedema is characterized by a distinct systemic cytokine profile and metabolic activity of the stromal vascular fraction.