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People with schizophrenia die prematurely, yet regional differences are unclear. PRISMA 2020-compliant systematic review/random-effects meta-analysis of cohort studies assessing mortality relative risk (RR) versus any control group, and moderators, in people with ICD/DSM-defined schizophrenia, comparing countries and continents. We conducted subgroup, meta-regression analyses, and quality assessment. The primary outcome was all-cause mortality. Secondary outcomes were suicide-, /natural-cause- and other-cause-related mortality. We included 135 studies from Europe (n = 70), North-America (n = 29), Asia (n = 33), Oceania (n = 2), Africa (n = 1). In incident plus prevalent schizophrenia, differences across continents emerged for all-cause mortality (highest in Africa, RR=5.98, 95 %C.I.=4.09-8.74, k = 1, lowest in North-America, RR=2.14, 95 %C.I.=1.92-2.38, k = 16), suicide (highest in Oceania, RR=13.5, 95 %C.I.=10.08-18.07, k = 1, lowest in North-America, RR=4.4, 95 %C.I.=4.07-4.76, k = 6), but not for natural-cause mortality. Europe had the largest association between antipsychotics and lower all-cause mortality/suicide (Asia had the smallest or no significant association, respectively), without differences for natural-cause mortality. Higher country socio-demographic index significantly moderated larger suicide-related and smaller natural-cause-related mortality risk in incident schizophrenia, with reversed associations in prevalent schizophrenia. Antipsychotics had a larger/smaller protective association in incident/prevalent schizophrenia regarding all-cause mortality, and smaller protective association for suicide-related mortality in prevalent schizophrenia. Additional regional differences emerged in incident schizophrenia, across countries, and secondary outcomes. Significant regional differences emerged for all-cause, cause-specific and suicide-related mortality. Natural-cause death was homogeneously increased globally. Moderators differed across countries. Global initiatives are needed to improve physical health in people with schizophrenia, local studies to identify actionable moderators., Competing Interests: Declaration of Competing Interest MS has been a consultant and/or advisor to or have received honoraria from Angelini, Lundbeck, Otsuka. EV has received grants and served as consultant, advisor or CME speaker for the following entities: Abbott, Allergan, Angelini, Dainippon Sumitomo Pharma, Janssen, Lundbeck, Novartis, Otsuka, Raffo, Richter, Sage, Sanofi-Aventis, and Takeda, unrelated to the present work. PFP has received advisory consultancy fees from Lundbeck outside of this work. CUC has been a consultant and/or advisor to or has received honoraria from: AbbVie, Acadia, Alkermes, Allergan, Angelini, Aristo, Axsome, Boehringer-Ingelheim, Cardio Diagnostics, Cerevel, CNX Therapeutics, Compass Pathways, Damitsa, Gedeon Richter, Hikma, Holmusk, IntraCellular Therapies, Janssen/J&J, Karuna, LB Pharma, Lundbeck, MedAvante-ProPhase, MedInCell, Medscape, Merck, Mindpax, Mitsubishi Tanabe Pharma, Mylan, Neurocrine, Noven, Otsuka, Pfizer, Pharmabrain, PPD Biotech, Recordati, Relmada, Reviva, Rovi, Seqirus, Servier, SK Life Science, Sumitomo Dainippon, Sunovion, Sun Pharma, Supernus, Takeda, Teva, and Viatris. He provided expert testimony for Janssen and Otsuka. He served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, and Teva. He has received grant support from Janssen and Takeda. He received royalties from UpToDate and is also a stock option holder of Cardio Diagnostics, Mindpax, and LB Pharma. 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). PG received fees for presentations at congresses or participation in scientific boards from Alcediag-Alcen, Angelini, GSK, Janssen, Lundbeck, Otsuka, SAGE, and Servier. HT reports personal fees from Janssen-Cilag and Otsuka and has participated in research projects funded by grants from Janssen Cilag and Eli Lilly to her employing institution. JT has participated in research projects funded by grants from Janssen Cilag and Eli Lilly to his employing institution. Dr. Tiihonen reports personal fees from the European Medicines Agency, Eli Lilly, Janssen Cilag, Lundbeck, Otsuka, Evidera, Mediuutiset, Sidera, and Sunovion. EDR has served as a speaker for Shire Sweden AB outside the submitted work. CAH has received speaker's honoraria for Medice. PL reports receiving grants from Novartis AG for the work submitted and grants from AstraZeneca, MSD, EFPIA, and IPHA outside the submitted work. MM received honoraria/has been a consultant for Angelini and Lundbeck outside of the present work. Henrik Larsson reports receiving grants from Shire Pharmaceuticals; personal fees from and serving as a speaker for Medice, Shire/Takeda Pharmaceuticals and Evolan Pharma AB; all outside the submitted work. Henrik Larsson is editor-in-chief of JCPP Advances. All other authors have nothing to disclose., (Copyright © 2023. Published by Elsevier B.V.)