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What Is Known and Objective: Exenatide is widely used in the treatment of type 2 diabetes mellitus (T2DM) because of its established effect on lowering glucose and promotion of weight loss. However, therapeutic response to exenatide varies considerably among patients with T2DM. The purpose of this study was to determine which variables can predict the response to exenatide and to individualize specific therapies for patients with T2DM who need treatment with exenatide., Methods: This is a retrospective cohort study of patients with T2DM who were treated with exenatide twice daily as a part of their diabetes care for at least 12 months. Patients were categorized into two cohorts based on glycaemic response to exenatide use: responders and non-responders., Results and Discussion: One hundred forty-eight patients met the inclusion criteria; among them, 92 responded with an HbA1C reduction ≥1.0% from baseline HbA1C and 56 did not respond to exenatide after 6 months of exenatide treatment. Binary logistic regression analysis revealed that baseline HbA1C and duration of diabetes were identified as predictors of HbA1C reduction ≥1% at 6 months (P < .05). Linear regression analysis further identified that patients with a higher baseline HbA1C (≥7.4%) and shorter duration of diabetes (≤15.0 years) were likely to respond to exenatide, whereas those with a lower baseline HbA1C (<7.4%) and longer duration of diabetes (>15.0 years) were not likely to respond to exenatide., What Is New and Conclusion: Our data indicate that T2DM patients with a higher baseline HbA1C and a shorter duration of diabetes are more likely to have a glycaemic response to exenatide than those with a lower baseline HbA1C and a longer duration of diabetes. The identification of predictors of therapeutic response to exenatide can provide clinically useful information for characterizing the patients who could receive the greatest benefit from exenatide., (© 2020 John Wiley & Sons Ltd.)