Semaglutide (Sema) improves glycemic control, reduces weight and exerts cardiovascular protection in type 2 diabetes (T2D), also acting on hepatic steatosis and inflammation. No data are, so far, available on the effect of Sema on oxidative stress, neither a comparison of oral (O) and injective (SC) formulations on these parameters has been performed. We analyzed the effect of Sema on metabolic and hepatic outcomes and markers of inflammation and oxidative stress, comparing standard doses of O or SC in targeting liver inflammation and fibrosis. We consecutively prescribed SC or O Sema in a 2:1 ratio to 33 subjects (age 66.8±6.9 yrs, BMI 30.3±5.2 kg/m2) (T0), longitudinally observing them for 6 months (T1). Anthropometry, biochemistry and transient elastography (TE) data were collected; hormones (Insulin, Glucagon, GIP, and GLP-1), inflammatory cytokines (TNFα, MCP-1, IL-10, IL-18) and peroxidation products (AGEs, TBARS, HNE) were measured. At baseline, O and SC cohorts were comparable, except for liver enzymes and Controlled Attenuation Parameter (CAP), a measure of liver steatosis (SC >O, both p<0.05). CAP correlated only with insulin and glucagon (R=0.42 and 0.61, p=0.045 and 0.005, respectively), while liver stiffness (LS) was related to AGEs levels (R=0.48, p=0.03). Differences emerged in T0-T1 variation between the formulations (better effect of SC on HbA1c [-13±11 vs -5±6 mmol/mol, p=0.0135], GPT [-16±29 vs -3±5 IU/L, p=0.048] and eGFR [+6±11 vs -1±4 ml/min/1.73m2, p=0.014]). CAP significantly decreased only in SC (from 330±14 to 304±13 dB/m, p=0.03). LS was significantly and similarly reduced by SC and O (-0.9±2.2 vs -0.4±1.3 kPa, p=ns). Insulin and GIP did not vary; glucagon declined (p=0.012). GLP-1 was strongly and similarly increased (by 116% by SC and by 130% by O). SC and O did not significantly modified TNFα, IL-10 and MCP-1 levels, while IL-18 was reduced only by SC (from 342±39 to 294±28 pg/ml, p=0.025). When exploring oxidative stress, AGEs were unaffected by Sema, while TBARS decreased in the whole study group, due to a powerful effect of SC (from 6.6±0.5 to 4.4±0.4 µM, p=0.002); HNE was strongly reduced by SC and O (both p<0.0001). SC Sema, better than O, improves metabolic control and keeps eGFR stable. SC and O similarly reduce LS, apparently linked to oxidative stress, as confirmed by the relevant anti-oxidative properties of the drug, never described in humans; SC is more effective than O in reducing TBARS.