Dercum's disease (DD) is a rare chronic disorder characterized by painful subcutaneous lipomas, mostly affecting overweight or obese middle-aged women. The etiology remains unclear, and evidence for medical treatments is limited. Surgical approaches may reduce pain but are associated with frequent relapses and are difficult to implement in extensive clinical pictures. We investigated the outcomes of multiple medical and surgical therapeutic strategies. Particularly, we explored immunomodulators (methotrexate and infliximab), used alone or combined with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) such as semaglutide, as well as the dual GIP (glucose-dependent insulinotropic polypeptide)/GLP-1 RAs tirzepatide. Five patients with DD were included in this retrospective single-center case series. Baseline clinical data, medical history, and longitudinal information on Dermatology Life Quality Index (DLQI), Visual Analogue Scale (VAS) for pain, and body mass index (BMI) were collected from existing medical records and scheduled follow-up visits conducted since 2021. Clinical trajectories differed across patients and regimens. Methotrexate and infliximab coincided with variable and often transient improvements in pain and quality of life. Combination regimens including GLP-1 RAs were accompanied by weight reduction and, in selected patients, by sustained improvements in pain and DLQI. In other cases, the benefit was limited or absent. Adverse events were manageable and consistent with the known safety profiles of these drugs. In this small real-world case series, therapeutic responses in DD were highly individualized, underscoring the absence of standardized medical treatment and the need for patient-tailored strategies. The observed patterns suggest that immunomodulatory and incretin-based therapies may represent exploratory options in selected patients, especially when surgery is not feasible. However, controlled studies are needed to clarify their role.