Abstract Disclosure: E. Camajani: None. S. Proietti: None. A. Persichetti: None. A. Feraco: None. A. Armani: None. L. Baccaro: None. M. Lombardo: None. S. Basciani: None. M. Caprio: None. Metabolic Syndrome (MetS) is characterized by the association of insulin resistance, hypertension, dyslipidemia, non-alcoholic fatty liver disease, impaired glucose tolerance, and is strictly related to increased cardiovascular risk. Recent scientific evidence confirms that very low calorie ketogenic diet (VLCKD) is a valuable treatment for patients with insulin resistance and visceral obesity. After the VLCKD phase it is essential to gradually reintroduce carbohydrates and increase calories in order to switch towards a Mediterranean nutritional approach. The aim of this study was to evaluate the efficacy and durability of a VLCKD protocol on cardiometabolic parameters related to the MetS. Twentynine patients with MetS, obesity and insulin resistance [12 males and 17 females, homeostatic model assessment index (HOMA) ≥ 2.5, age 56.7 ± 6.4 years, body mass index (BMI) 35.3± 3.9 kg/m2)] followed a VLCKD for 45 days (≤800 kcal/day). After the VLCKD phase (45 days), they followed a low calorie diet (LCD, 1100-1200Kcal) with a low carbohydrate content (60-80g/day) for 45 days. Subsequently, patients were switched to a hypocaloric Mediterranean diet (HMD-1500 Kcal) with 120-130g/day carbohydrate content and monitored till for additional 60 days (150 days). Anthropometric indexes, blood and urine chemistry, and body composition were assessed. Results: Body weight [−8.7±3.3, p<0.001], BMI [−3.2±1.0 kg/m2, p<0.001], blood pressure (-9.1±14.2 mmHg, p=0.002], waist circumference [-6.4±3.0 cm, p<0.001], HOMA index [-4.3±5.8, p<0.001], insulin [-13.6±14.4 µIU, p<0.001], total and low-density lipoprotein cholesterol (LDL) [-49.5±31.2 mg, p<0.001; -36.7±20.6 mg, p<0.001 respectively] and triglycerides [-65.9±93.6 mg, p<0.001] markedly decreased in all participants during the VLCKD phase (day 45). Importantly, body weight [-3.5±1.7 Kg, p<0.001], BMI [-1.3±0.6 kg/m2, p<0.001], total and LDL cholesterol [-21.4±20.8 mg, p<0.001; -19.2±17.2 mg, p<0.001, respectively] showed a further significance decrease during the LCD phase (day 90), as compared to the end of VLCKD phase. Noteworthy, a significant reduction of visceral adipose tissue (VAT) was observed at the end of VLCKD phase [-103.5±128.7 cm3, p<0.001], as well as the end of LCD phase [-80.5±120.3 cm3, p=0.002]. Importantly, a trend in body weight reduction [-0.6±1.5 Kg, p=0.125] was observed at the end of the HMD phase (day 150), compared with the end of the LCD phase (day 90). Our study confirms that VLCKD protocol is an effective strategy in the management of obesity and its metabolic comorbidities, due to its pleiotropic effects, particularly on the reduction of visceral adipose tissue. Indeed, favourable effects on body weight and metabolic risk factors persist also after the reintroduction of carbohydrates and the switch to a HMD. Presentation: Friday, June 16, 2023