Objective Very low-carbohydrate ketogenic diets (VLCKDs) are a new type of weight loss (WL) intervention for severe obesity and are associated with a significant improvement in non-alcoholic fatty liver disease (NAFLD).Little is known about the effect of sex differences on weight loss induced by following a VLCKD.The aim of this study was to investigate the effects of sex differences on weight loss and NAFLD improvement in patients with severe obesity undergoing a VLCKD. Methods and procedures Seventy-three patients (42 females and 28males) with morbid obesity (BMI 40kg/m2 or 35 kg/m2+comorbidity) eligible for sleeve gastrectomy underwent a 25-day-long VLCKD.Anthropometric parameters, peripheral BP, bioimpedentiometry, degree of liver steatosis measured by ultrasonography, liver function tests, and glucose homeostasis were measured before and after the VLCKD. Results Males experienced a significantly larger excess body weight loss (EBWL, 14.5 vs11.7% respectively,p=0.018) and a greater reduction in y-glutamyl transferase (ϒ-GT, 17 vs6 IU/L respectively,p=0.003) than females. Dividing the female group by menopausal status, a significant difference between males and pre-menopausal females was found for both EBWL (14.5 vs10.8% respectively,p=0.017) and ϒ-GT (17 vs3 IU/L respectively,p Conclusion The efficacy of VLCKD in severe obesity is influenced by sex differences and, for females, by menopausal status. Males seem to experience larger benefits than females in terms of EBWL and NAFLD improvement. These differences seems attenuated after menopause, probably because of changes in hormonal profile and body composition.