Summary Aims To evaluate in a real‐world setting the effectiveness of two drugs, orlistat and liraglutide, in patients with overweight or obesity and insufficient weight loss (WL) after a lifestyle modification programme. Methods Retrospective, observational cohort study comparing clinical outcomes of orlistat 120 mg three times a day and liraglutide (up to 3 mg daily) in adult patients with BMI ≥30 kg/m2 or ≥27 kg/m2 with at least a weight‐related comorbidity who had failed to lose at least 5% of their weight after 6 months of lifestyle modification. The co‐primary end‐points, assessed at 3‐6 months and at the end of the follow‐up, were weight change from baseline, proportion of patients who lost at least 5% of their baseline weight and adjusted differences in WL between both drugs. Results Five hundred patients, 400 in the group of orlistat (age 47.0, weight 107.8 kg) and 100 in the group of liraglutide (age 51.9 years, weight 105.1 kg), were included. Treatment with both drugs significantly reduced weight, fasting plasma glucose, systolic BP, low‐density lipoprotein‐cholesterol and alanine transaminase over a median follow‐up period of 7 months. WL with liraglutide (−7.7 kg) was significantly greater than that observed with orlistat (−3.3 kg), and more individuals lost at least 5% of their baseline weight with liraglutide (64.7%) than with orlistat (27.4%). Rates of prediabetes significantly decreased with liraglutide in comparison to orlistat. Conclusions In this real‐world study, liraglutide showed a greater effectiveness in WL compared with orlistat and improved several obesity‐associated metabolic and cardiovascular risk factors.