Endoscopic sleeve gastroplasty (ESG) is one of the new minimally invasive endoscopic treatments aimed at inducing weight loss. Its effectiveness in terms of weight loss is proven. Gastric volume reduction and delayed gastric emptying are the mechanisms that drive weight loss. However, potential benefits for co-morbidities in relation to weight loss after ESG are still being investigated. This study aims to evaluate the effect of ESG procedures on major obesity-associated co-morbidities, and on some biological parameters. This is a series of consecutive cases from a prospective observational study carried out in a specialized center that follows a standardized care pathway for the multimodal management of obesity. Patients who have undergone ESG with endoscopic and laboratory follow-up at six and twelve months after this intervention were included in the study. Prospectively recorded data on weight loss, co-morbidities and laboratory parameters at six and twelve months after surgery was analyzed retrospectively. Changes in body mass index (BMI), absolute weight loss (AWL), percent of excess weight loss (%EWL) and percent total weight loss (%TWL) were assessed at six and twelve months. Reduction in various obesity-related co-morbidities (arterial hypertension [AHT], type 2 diabetes mellitus [T2DM], gastroesophageal reflux disease [GERD], obstructive sleep apnea syndrome [OSAS] and dyslipidemia was also evaluated at six and twelve months. Changes in blood glucose, liver function tests and lipid blood tests were also analyzed at six and twelve months. From October 2016 to July 2021, 99 of the 227 patients who underwent ESG in our unit (43.6%) subsequently underwent a complete endoscopic and laboratory follow-up at six and twelve months. The initial BMI was 42.7±7.8kg/m2 and age was 45±12.7 years. Seventy-four patients (74.8%) were female. Total weight loss (%TWL) and excess weight loss (%EWL) were 16.6±7.4% and 43.3±21.2%, respectively, at six months, 16.6±9.6% and 42.9±25.6%, respectively, at one year. At six and twelve month follow-up, a statistically significant reduction was observed for the rates of T2DM (30.8 and 32.7%), hypertension (18.4 and 22.1%), GERD (28 and 25.7%), OSAS (15.8 and 25.5%) and dyslipidemia (69.2 and 77.2%) (P<0.001). A statistically significant difference was found in the reduction in blood glucose between the pre-operative period and six months post-operatively (P<0.01) and between the pre-operative period and twelve months post-operatively (P<0.01). The reduction in triglycerides and total cholesterol between the pre-operative values and at six months was statistically significant (P<0.01) as was the reduction at twelve months (P<0.01) (P=0.017). For liver function tests, the reduction in AST was statistically significant at six and twelve months after ESG (P=0.048) (P=0.048) as was ALT (P<0.01) (P<0.01) respectively. From October 2016 to July 2021, of the 227 patients who underwent ESG, 99 (43.6%) had follow-up gastro-duodenoscopy at 6 and 12 months. %TWL and %EWL were respectively 16.6±7.4% and 43.3%±21.2 at 6 months, 16.6±9.6% and 42.9±25.6% at one year. Statistically significant reduction rates at 6 and 12 months were observed in T2DM (30.8 and 32.7%), AHT (18.4 and 22.1%), GERD (28 and 25.7%), OSAS (15.8 and 25.5%) and dyslipidemia (69.2 and 77.2%) (P<0.001). Moreover, glycemic levels were statistically significantly reduced between the pre-operative period and 6 months post-operative (1.11±0.22mg/L vs. 1.01±0.17mg/L, P<0.01), and between the pre-operative period and 12 months post-operative (1.11±0.22mg/L vs. 1.06±0.32mg/L, P<0.01). A statistically significant reduction was also observed in triglycerides and total cholesterol levels at 6 months (1.52±0.74mmol/L vs. 1.14±0.52mmol/L, P<0.01) (1.94±0.4mmol/L vs. 1.85±0.36mmol/L, P<0.01) and at 12 months (1.52±0.74mmol/L vs. 1.18±0.67mmol/L, P<0.01) (1.94±0.4mmol/L vs. 1.82±0.39mmol/L, P=0.017) and in AST (27.2±11.7 IU/L vs. 23.7 IU/L; P=0.048) (27.2±11.7 IU/L vs. 24.7±14.65 IU/L, P=0.048) and ALAT levels (34±21.32 IU/L vs. 22.3±10.4 IU/L, P<0.01 and 34±21.32 IU/L vs. 27.07±25 IU/L, P<0.01) at 6 and 12 months after ESG, respectively. ESG is a well-tolerated and safe surgical procedure that is effective in terms of weight loss and reduction of obesity-related co-morbidities at six months and one year. This procedure could thus be adopted on a broader clinical scale and be more widely promoted as an effective treatment for morbid obesity.