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Background: Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication., Methods: EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete., Findings: Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94-1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ 2 =1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study., Interpretation: We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice., Funding: Lundbeck and Otsuka., Competing Interests: Declaration of interests SG reports consulting fees from Angelini, Janssen Pharmaceuticals, Gedeon-Richter, Recordati, and Innova Pharma; and honoraria and expenses from Angelini, Gedeon-Richter, Recordati, Janssen Pharmaceuticals, Janssen-Cilag, Lundbeck, Lundbeck Italia, and Sunovion. SL reports payments to the institution from European Group for Research In Schizophrenia for the conduct of the trial; consulting fees from Alkermes, Angelini, Lundbeck, Lundbeck Foundation, Otsuka, Recordati, Rovi, and Teva; and honoraria for lectures from Angelini, Eisai, Gedeon, Lundbeck, Medichem, Merck, Mitsubishi, Otsuka, Recordati, and Sanofi-Aventis. IB reports grants from the EU to the Semmelweise University; royalties from Oxford University for a published book (editor); consulting fees from Gedeon Richter, Janssen, Janssen Cilag; speaker fees from Hikma Janssen, Janssen Cilag, Gedeon Richter, Medichem Pharmaceuticals by Unilab, and Mitsubishi Tanabe Pharma Signapure; and leadership or fiduciary roles with European College of Neuropsychopharmacology, the European Psychiatry Association, and Clincal Pharmacological Ethics Committee and Medical Research Council (Hungary). BG has been the leader of a Lundbeck Foundation Centre of Excellence for Clinical Intervention and Neuropsychiatric Schizophrenia Research (January, 2009–December, 2021), which was partially financed by an independent grant from the Lundbeck Foundation based on international review and partially financed by the Mental Health Services in the Capital Region of Denmark, the University of Copenhagen, and other foundations; all grants are the property of the Mental Health Services in the Capital Region of Denmark and administrated by them. AH reports speaker fees from Lundbeck, Otsuka, Janssen, Recordati, and Rovi; was member of advisory boards for Lundbeck, Otsuka, Janssen, Recordati, and Rovi; and is an Editor of the German Association of Scientific Medical Societies in Germany and World Federation of Societies of Biological Psychiatry schizophrenia guidelines. GP reports honoraria from Lundbeck, Janssen, Schwabe Austria; support for attending meetings from Schwabe Austria; being president at the Austrian Society for Social Psychiatry and Gerontopsychiatry; and stock with Janssen. PR reports an advisory board role for Angelini. NS reports honoraria for lectures from Recordati Hellas, BGP Pharmaceuticals, Lundbeck Hellas, and Vianex. MD is an employee of Minerva Neurosciences with stock options. RSK reports consulting fees from Alkermes, Sunovion, Gedeon-Richter, and Otsuka. WWF reports consultant fees from Angelini, Richter, Recordati, Lundbeck, Otsuka, Teva, Boehringer-Ingelheim, Pierre Fabre, Janssen, Sunovion, Dainippon-Sumitomo, Takeda, and Pfizer; speaker fees from Janssen, Lundbeck, Otsuka, Richter, and Recordati; and grants from Janssen, Lundbeck, and Otsuka. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)