To evaluate in a real-world setting the effectiveness of exenatide once-weekly (ExQW) in patients with T2D and to determine predictors of glycaemic and weight response to this drug at 6months. Observational, retrospective, multicenter study in adult patients with T2D and BMI ≥30kg/m2 from 4 tertiary Spanish hospitals who started ExQW therapy at least 6months before the inclusion and had not achieved adequate glycaemic control on oral therapies or other GLP-1 receptor agonists. Glycaemic response was defined as an A1C reduction ≥1.0% and weight response as a weight loss ≥3% 6months after ExQW. The best predictive models of glycaemic and weight response were estimated by binary logistic regression. One hundred and forty eight patients were included, mean age 58.0years, A1C 7.7%, weight 105.9kg and BMI 38.4kg/m2 . A1C (-1.1%), weight (-3.9kg), systolic blood pressure (-4.0mm Hg), diastolic blood pressure (-2.9mm Hg), LDL-cholesterol (-14.2mg/dL) and triglycerides (-31.0mg/dL) significantly decreased 6months after ExQW. 41.5% of patients had an A1C reduction ≥1.0% and 53.1% lost ≥3% of baseline weight. Glycaemic and weight reductions were sustained in patients completing 1 and 2years of follow-up. The best predictive model of glycaemic response only included higher A1C levels (OR 3.9), whereas higher BMI (OR 1.1) and prior DPP-4i therapy (OR 3.1) were associated to weight response in the multivariate analysis. In a real-world setting, ExQW significantly decreased A1C, weight, blood pressure and lipids at 6months. Our study identified higher baseline A1C as the sole independent predictor of glycaemic response to ExQW and higher BMI and previous DDP4i treatment as predictive factors of meaningful weight response.