Patients with schizophrenia have a higher mortality risk than patients suffering from any other psychiatric disorder. Previous research is inconclusive regarding the association of antipsychotic treatment with long-term mortality risk. To this aim, we systematically reviewed the literature and performed a meta-analysis on the relationship between long-term mortality and exposure to antipsychotic medication in patients with schizophrenia. The objectives were to (i) determine long-term mortality rates in patients with schizophrenia using any antipsychotic medication; (ii) compare these with mortality rates of patients using no antipsychotics; (iii) explore the relationship between cumulative exposure and mortality; and (iv) assess causes of death. We systematically searched the EMBASE, MEDLINE and PsycINFO databases for studies that reported on mortality and antipsychotic medication and that included adults with schizophrenia using a follow-up design of more than 1 year. A total of 20 studies fulfilled our inclusion criteria. These studies reported 23,353 deaths during 821,347 patient years in 133,929 unique patients. Mortality rates varied widely per study. Meta-analysis on a subgroup of four studies showed a consistent trend of an increased long-term mortality risk in schizophrenia patients who did not use antipsychotic medication during follow-up. We found a pooled risk ratio of 0.57 (LL:0.46 UL:0.76 p value <0.001) favouring any exposure to antipsychotics. Statiscal heterogeneity was found to be high (Q = 39.31, I
2 = 92.37%, p value < 0.001). Reasons for the increased risk of death for patients with schizophrenia without antipsychotic medication require further research. Prospective validation studies, uniform measures of antipsychotic exposure and classified causes of death are commendable.