Aim: Liraglutide and lixisenatide improved glycemic control, weight and cardiovascular risk factors (CVRF) in type 2 diabetes mellitus (T2DM) patients. Our objective was to analyze clinical efficacy and safety differences in routine clinical practice., Methods: A 24-week prospective observational study to compare the effect of liraglutide versus lixisenatide in obese T2DM patients in routine clinical practice. The main objective was to analyze between-group glycosylated hemoglobin (HbA 1c ) differences at the end of the study. Secondary objectives included differences in body weight, other CVRF, changes in medication, side effects, satisfaction and safety., Results: A total of 100 patients (50 liraglutide, 50 lixisenatide) were included. Both groups experienced a decrease in HbA 1c values (liraglutide, -1.4%, CI 95% -2, -0.8, P < 0.001 vs. lixisenatide, -0.8%, 95% CI -1.2, -0.5, P < 0.001). No differences were found in final HbA 1c values between both groups (liraglutide 7.3 ± 0.9% vs. lixisenatide 7.2 ± 1.5%, P = 0.7). We did not detect between groups differences in anthropometric variables or CVRF at the study end. A lower proportion of patients received treatment with a maximum dose of liraglutide compared with lixisenatide (27% vs. 95%, P < 0.001). In contrast, a greater percentage of patients in the lixisenatide group than in liraglutide group (29% vs. 9%, P = 0.026) intensified treatment by the addition of sodium-glucose transporter type 2 inhibitors. Adverse events were less frequently reported in liraglutide treated patients compared with lixisentatide (80% vs. 96%, P = 0.014). No serious adverse events were detected., Conclusions: These results confirm the efficacy and safety of liraglutide and lixisenatide in routine clinical practice. Moreover, a different therapeutic effect between liraglutide and lixisenatide was detected., (Copyright © 2019 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.)