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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. [ABSTRACT FROM AUTHOR]