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We analyzed the medical condition of 360 women affected by lipedema of the lower limbs in stages 1, 2, and 3. The data were assessed for the whole population and compared between different clinical stages, distinguishing between obese and non-obese patients. The most frequent clinical signs were pain when pinching the skin, subcutaneous nodules, and patellar fat pads. The most frequently painful site of the lower limbs was the medial lower third of the thigh. The pain score obtained on lower limb points increased progressively with the clinical stage. In all points evaluated, the thickness of the subcutaneous tissue increased with the clinical stage. Analyzing the data on the lower medial third of the leg and considering only patients with type 3 lipedema, the difference between stages was statistically significant after correction for age and BMI. We found higher levels of C-reactive protein at more severe clinical stages, and the difference was significant after correction for age and BMI between the stages. Overall, the prevalence of alterations of glucose metabolism was 34%, with a progressive increase in prevalence with the clinical stage. The most frequent comorbidities were vitamin D insufficiency, chronic venous disease, allergies, dyslipidemia, headache, and depression of mood. Interestingly, in comparison with the general population, we found higher prevalence of chronic autoimmune thyroiditis and polycystic ovary syndrome. Finally, the clinical stage and the involvement of the upper limbs or obesity suggest a worse clinical, anthropometric, and endocrine–metabolic profile.