People with schizophrenia die 15â20 years prematurely. Understanding mortality risk and aggravating/attenuating factors is essential to reduce this gap. We conducted a systematic review and randomâeffects metaâanalysis of prospective and retrospective, nationwide and targeted cohort studies assessing mortality risk in people with schizophrenia versus the general population or groups matched for physical comorbidities or groups with different psychiatric disorders, also assessing moderators. Primary outcome was allâcause mortality risk ratio (RR); key secondary outcomes were mortality due to suicide and natural causes. Other secondary outcomes included any other specificâcause mortality. Publication bias, subgroup and metaâregression analyses, and quality assessment (NewcastleâOttawa Scale) were conducted. Across 135 studies spanning from 1957 to 2021 (schizophrenia: N=4,536,447; general population controls: N=1,115,600,059; other psychiatric illness controls: N=3,827,955), allâcause mortality was increased in people with schizophrenia versus any nonâschizophrenia control group (RR=2.52, 95% CI: 2.38â2.68, n=79), with the largest risk in firstâepisode (RR=7.43, 95% CI: 4.02â13.75, n=2) and incident (i.e., earlierâphase) schizophrenia (RR=3.52, 95% CI: 3.09â4.00, n=7) versus the general population. Specificâcause mortality was highest for suicide or injuryâpoisoning or undetermined nonânatural cause (RR=9.76â8.42), followed by pneumonia among natural causes (RR=7.00, 95% CI: 6.79â7.23), decreasing through infectious or endocrine or respiratory or urogenital or diabetes causes (RR=3 to 4), to alcohol or gastrointestinal or renal or nervous system or cardioâcerebrovascular or all natural causes (RR=2 to 3), and liver or cerebrovascular, or breast or colon or pancreas or any cancer causes (RR=1.33 to 1.96). Allâcause mortality increased slightly but significantly with median study year (beta=0.0009, 95% CI: 0.001â0.02, p=0.02). Individuals with schizophrenia <40 years of age had increased allâcause and suicideârelated mortality compared to those â„40 years old, and a higher percentage of females increased suicideârelated mortality risk in incident schizophrenia samples. Allâcause mortality was higher in incident than prevalent schizophrenia (RR=3.52 vs. 2.86, p=0.009). Comorbid substance use disorder increased allâcause mortality (RR=1.62, 95% CI: 1.47â1.80, n=3). Antipsychotics were protective against allâcause mortality versus no antipsychotic use (RR=0.71, 95% CI: 0.59â0.84, n=11), with largest effects for secondâgeneration longâacting injectable antiÂpsychotics (SGAâLAIs) (RR=0.39, 95% CI: 0.27â0.56, n=3), clozapine (RR=0.43, 95% CI: 0.34â0.55, n=3), any LAI (RR=0.47, 95% CI: 0.39â0.58, n=2), and any SGA (RR=0.53, 95% CI: 0.44â0.63, n=4). Antipsychotics were also protective against natural causeârelated mortality, yet firstâgeneration antipsychotics (FGAs) were associated with increased mortality due to suicide and natural cause in incident schizophrenia. Higher study quality and number of variables used to adjust ...