The objective of this study was to assess changes in body composition, with a specific focus on fat mass (FM) and fat-free mass (FFM), in obese adults with type 2 diabetes (T2D) treated with once-weekly (OW) subcutaneous (s.c.) semaglutide. This was a single-center, 12-month, real-world, ambispective study (6-month prospective and 6-month retrospective). Body composition parameters were assessed via segmental multifrequency bioelectrical impedance analysis (SMF-BIA). A total of 117 patients with DM2, with a median age of 56 years, a median HbA1c level of 9.4%, and a median body weight of 102.5 kg, were included in the study. The median body weight, body fat mass, and visceral fat significantly decreased at 6 months, with values of -9.3, -7.5, and -1.8 kg, respectively. There were further reductions from 6 to 12 months, albeit at a slower rate. The median skeletal muscle mass significantly decreased at 6 months (-1.2 kg), although no further significant reductions were observed at 12 months. OW s.c. semaglutide for 12 months significantly improved body composition parameters, mainly at the expense of fat mass loss, with the preservation of skeletal muscle mass. These changes are clinically meaningful, since they impact general metabolic health and are associated with improvements in metabolic control and clinical parameters associated with renal and CV risks, as well as presumable improvements in quality of life.