Introduction This study aimed to demonstrate the beneficial effect of lixisenatide as add-on therapy to oral antidiabetics (OADs) in type 2 diabetes mellitus (T2DM) patients in routine clinical practice in Bulgaria. Methods This was a prospective, observational, multicentre study evaluating the real-life effectiveness and safety of 24-week treatment with lixisenatide in previously uncontrolled T2DM patients on combination therapy with metformin and sulfonylurea on highest tolerable doses. Results A total of 262 patients were included in the study. The mean (± SD) age in the cohort was 56.2 ± 9.1 years. The mean duration of diabetes was 7.3 ± 6.0 years. The mean body mass index (BMI) was 39.7 ± 4.7 kg/m 2 . The mean glycated haemoglobin (HbA1c) at baseline was 8.8 ± 1.1%. The mean fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) at baseline were 10.5 ± 3.1 mmol/L and 12.1 ± 3.4 mmol/L respectively. The proportion of patients achieving HbA1c < 7% at study end was 39.0% (95% CI 32.9–45.3). The proportion of patients reaching their individual HbA1c target was 49.0% (95% CI 42.6–55.4). The mean change in HbA1c from baseline was − 1.3 ± 1.2%. The mean change in FPG was − 2.4 ± 3.0 mmol/L and the mean change in PPG was − 3.2 ± 3.6 mmol/L. The mean body weight change from baseline was − 7.2 ± 5.5 kg. The mean BMI change was − 2.6 ± 1.9 kg/m 2 . The hypoglycaemia incidence was low: 6.1% for all hypoglycaemic events, 3.8% for symptomatic events and 0.4% for severe events. Conclusions Lixisenatide as add-on therapy to OADs in a real-life setting led to significant improvements in glycaemic control with low incidence of hypoglycaemia and beneficial weight loss. Lixisenatide was well tolerated with few patients having adverse events or discontinuing therapy. These findings are consistent with lixisenatide’s safety and efficacy profile established in randomized controlled trials (RCTs). Funding Sanofi Bulgaria. Electronic supplementary material The online version of this article (10.1007/s13300-019-0603-9) contains supplementary material, which is available to authorized users.