Two antiplatelet agents are better than one for preventing recurrent stroke after acute ischaemic stroke or transient ischaemic attack (TIA). Therefore, intensive treatment with three agents might be better still, providing it does not cause undue bleeding. To compare the safety and efficacy of intensive therapy with guideline antiplatelet therapy for acute ischaemic stroke and TIA. International prospective randomised open-label blinded end-point parallel-group superiority clinical trial. Acute hospitals at 106 sites in four countries. Patients &gt; 50 years of age with acute non-cardioembolic ischaemic stroke or TIA within 48 hours of ictus (stroke). Participants were allocated at random by computer to 1 month of intensive (combined aspirin, clopidogrel and dipyridamole) or guideline (combined aspirin and dipyridamole, or clopidogrel alone) antiplatelet agents, and followed for 90 days. The primary outcome was the incidence and severity of any recurrent stroke (ischaemic, haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days by blinded telephone follow-up. Analysis using ordinal logistic regression was by intention to treat. Other outcomes included bleeding and its severity, death, myocardial infarction (MI), disability, mood, cognition and quality of life. The trial was stopped early on the recommendation of the Data Monitoring Committee after recruitment of 3096 participants (intensive, <i>n</i> = 1556; guideline, <i>n</i> = 1540) from 106 hospitals in four countries between April 2009 and March 2016. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy in 3070 (99.2%) participants with data [93 vs. 105 stroke/TIA events; adjusted common odds ratio 0.90, 95% confidence interval (CI) 0.67 to 1.20; <i>p</i> = 0.47]. Major (encompassing fatal) bleeding was increased with intensive as compared with guideline therapy [39 vs. 17 participants; adjusted hazard ratio (aHR) 2.23, 95% CI 1.25 to 3.96; <i>p</i> = 0.006]. There were no differences between the treatment groups in all-cause mortality, or the composite of death, stroke, MI and major bleeding (aHR 1.02, 95% CI 0.77 to 1.35; <i>p</i> = 0.88). Patients and investigators were not blinded to treatment. The comparator group comprised two guideline strategies because of changes in national guidelines during the trial. The trial was stopped early, thereby reducing its statistical power. The use of three antiplatelet agents is associated with increased bleeding without any significant reduction in recurrence of stroke or TIA. The safety and efficacy of dual antiplatelet therapy (combined aspirin and clopidogrel) versus aspirin remains to be defined. Further research is required on identifying individual patient response to antiplatelets, and the relationship between response and the subsequent risks of vascular recurrent events and bleeding complications. Current Controlled Trials ISRCTN47823388. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in <i>Health Technology Assessment</i>; Vol. 22, No. 48. See the NIHR Journal Library website for further project information. The Triple Antiplatelets for Reducing Dependency after Ischaemic Stroke (TARDIS) vanguard phase was funded by the British Heart Foundation (grant PG/08/083/25779, from 1 April 2009 to 30 September 2012) and indirect funding was provided by the Stroke Association through its funding of the Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK. There was no commercial support for the trial and antiplatelet drugs were sourced locally at each site. The trial was sponsored by the University of Nottingham.