Summary Background Exenatide is an incretin mimetic that shares glucoregulatory properties with glucagon-like peptide 1 (GLP-1), and improves glycaemic control, with progressive bodyweight reductions, when administered twice a day in patients with type 2 diabetes. We compared the efficacy of a once-weekly formulation of exenatide to that of a twice daily dose. Methods A 30-week, randomised, non-inferiority study compared a long-acting release formulation of exenatide 2 mg administered once weekly to 10 μg exenatide administered twice a day, in 295 patients with type 2 diabetes (haemoglobin A1c HbA1c 8·3% SD 1·0, mean fasting plasma glucose 9 SD 2 mmol/L, weight 102 SD 20 kg, diabetes duration 6·7 SD 5·0 years). The patients were naive to drug therapy, or on one or more oral antidiabetic agents. The primary endpoint was the change in HbA1c at 30 weeks. This study is registered with ClinicalTrials.gov , number NCT00308139. Findings At 30 weeks, the patients given exenatide once a week had significantly greater changes in HbA1c than those given exenatide twice a day (−1·9 SE 0·1% vs −1·5 0·1%, 95% CI −0·54% to −0·12%; p=0·0023). A significantly greater proportion of patients receiving treatment once a week versus twice a day achieved target HbA1c levels of 7·0% or less (77% vs 61% of evaluable patients, p=0·0039). Interpretation Exenatide once weekly resulted in significantly greater improvements in glycaemic control than exenatide given twice a day, with no increased risk of hypoglycaemia and similar reductions in bodyweight. Funding Amylin Pharmaceuticals Inc and Eli Lilly and Company.