Background: Compelling evidence shows that appropriate use of anticoagulation in patients with nonvalvular atrial fibrillation reduces the risk of ischaemic stroke by 67% and all-cause mortality by 26%. Despite this evidence, anticoagulation is substantially underused, resulting in avoidable fatal and disabling strokes.Methods: DESPATCH is a cluster randomised controlled trial with concealed allocation and blinded outcome assessment designed to evaluate a multifaceted and tailored implementation strategy for improving the uptake of anticoagulation in primary care. We have recruited general practices in South Western Sydney, Australia, and randomly allocated practices to receive the DESPATCH intervention or evidence-based guidelines (control). The intervention comprises specialist decisional support via written feedback about patient-specific cases, three academic detailing sessions (delivered via telephone), practice resources, and evidence-based information. Data for outcome assessment will be obtained from a blinded, independent medical record audit. Our primary endpoint is the proportion of nonvalvular atrial fibrillation patients, over 65 years of age, receiving oral anticoagulation at any time during the 12-month posttest period.Discussion: Successful translation of evidence into clinical practice can reduce avoidable stroke, death, and disability due to nonvalvular atrial fibrillation. If successful, DESPATCH will inform public policy, providing quality evidence for an effective implementation strategy to improve management of nonvalvular atrial fibrillation, to close an important evidence-practice gap.Trial registration: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12608000074392.