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Background: Lipedema is a progressive disorder of subcutaneous connective tissue, predominantly affecting women, and characterized by an increase in subcutaneous adipose tissue, particularly in the lower body. This study aims to explore the gut microbiota (GM) profile in lipedema patients to characterize the associated GM and compare it with the control group. Methods: A prospective randomized case-control pilot study was conducted from September 2023 to May 2024, involving 55 Caucasian women, aged 20-60. The participants were divided into two groups: 35 with lipedema (LIPPY) and 20 controls (CTRL). Body composition was assessed using Dual X-ray Absorbimetry (DXA), and GM analysis was performed through 16S rRNA gene sequencing. Results: LIPPY subjects showed increased Intramuscular Adipose Tissue (IMAT) and reduced Lean Mass (LM)/Fat Mass (FM) ratios. While alpha and beta diversity metrics did not differ significantly between groups, differential abundance analysis identified a significant reduction in Eggerthellaceae (Log Fold Change (LFC) = -0.19, p = 0.04) and enrichment of Propionibacteriaceae (LFC = +0.18, p = 0.009) and Acidaminococcaceae (LFC = +0.32, p = 0.013) in the LIPPY group. Genus-level analysis showed a significant reduction in Blautia and Ruminiclostridium (LFC = -0.32 and -0.02; p = 0.02 and 0.04) and enrichment of Anaerostipes, Propionibacterium, and Phascolarctobacterium (LFC = +0.07, +0.17, and +0.34; p = 0.02, 0.005, 0.005, respectively). In correlation analyses, within LIPPY, Eggerthellaceae correlated negatively with Body Mass Index (BMI) (ρ = -0.61, p < 0.05) and positively with Appenicular (Appen) LM/Weight and AppenLM/BMI (ρ = +0.43 and +0.41, p < 0.05), while Anaerostipes correlated positively with these lean mass indices (ρ = +0.40, p < 0.05). In CTRL, only Anaerostipes showed a significant negative correlation with BMI (ρ = -0.64, p < 0.05). Conclusions: This study provides the first evidence of a distinct GM profile in LIPPY, with notable links to adverse body composition markers such as IMAT. Trial Registration: Trial registered on 24 June 2013 with ClinicalTrial.gov (NCT01890070).