Background: Trials of fluoxetine for recovery after stroke have reported conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to determine if daily fluoxetine for 6 months after acute stroke improves functional outcomes in an Australasian and Vietnamese population. Methods: AFFINITY was an international, multicentre, randomised, parallel-group, double-blind, placebo-controlled trial. Eligible adult patients with residual neurological impairment 2-15 days after stroke were randomised centrally using a minimisation algorithm to once daily, oral fluoxetine 20mg or matching placebo for 6 months. The primary outcome was functional recovery (modified Rankin scale, mRS) at 6 months. The primary analysis was an intention-to-treat, ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. The planned sample size was 1600 patients. Findings: 1280 patients were recruited in Australia (n=532), New Zealand (n=42) and Vietnam (n=706) between 11 January 2013 and 30 June 2019; 642 were allocated fluoxetine and 638 placebo. Adherence to trial medication (mean 167 [SD 48] days) was similar between groups. At 6 months, mRS data were available in 97.2% (fluoxetine) and 99.1% (placebo) of patients. The distribution of mRS categories at 6 months was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0.936, 95% CI 0.762-1.150; p=0.5296), and consistent in all pre-defined subgroups. Compared to placebo, patients allocated fluoxetine had more falls (3.12% vs 1.10%), bone fractures (2∙96% vs 0.94%) and seizures (1.56% vs 0.31%) at 6 months. Interpretation: Fluoxetine 20mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and seizures. These results do not support the use of fluoxetine for stroke recovery. Trial registration: The trial was registered with the Australian New Zealand Clinical Trials Registry, number ACTRN 12611000774921. Funding Statement: National Health and Medical Research Council of Australia (Project Grant 1059094). Declaration of Interests: Dr. Hankey reports grants from the National Health & Medical Research Council of Australia, Vetenskapsradet (The Swedish Research Council), and United Kingdom National Institute for Health Research Technology (NIHR), during the conduct of the study; and personal fees from American Heart Association, outside the submitted work. Dr. Hackett reports grants from National Health and Medical Research Council, during the conduct of the study. Dr. Etherton-Beer reports grants from National Health and Medical Research Council (NHMRC) of Australia, during the conduct of the study. Dr. Lung reports grants from Australian National Health and Medical Research Council, during the conduct of the study; other from George Health Enterprises, outside the submitted work; In addition, Dr. Lung has a patent Low-dose blood pressure lowering combination medications pending to George Health Enterprises. Dr. Anderson reports grants from National Health and Medical Research Council (NHMRC) of Australia, grants from Takeda, personal fees from Takeda, outside the submitted work. Drs Almeida, Flicker, Dennis, Ford, Billot, Jan, Murray, Lundstrom, Thang-Nguyen, and Gommans have nothing to disclose. Ethics Approval Statement: The trial protocol (supplementary appendix) was approved by the Royal Perth Hospital Ethics Committee on 24 February, 2012 (approval number EC2011/131). All participating sites subsequently received approval from their relevant ethics committee and institutional review board. Written informed consent was obtained from each patient or, if the patients were unable to provide consent, from their legally approved surrogate.