BackgroundPeople with severe mental illness (SMI) have a higher prevalence of several chronic physical health conditions, and the prevalence of physical multimorbidity is expected to rise. The aim of this study was to assess the strength of the association between SMI and physical multimorbidity.Study selection and analysisWe systematically searched PubMed/Medline, Scopus, Embase, Web of Science, PsycINFO and the behavioural sciences collection databases, from inception to 31 January 2023, for studies that investigated the association between SMI and physical multimorbidity. Humans of any age either clinically diagnosed and/or currently receiving treatment for SMI, specified as schizophrenia (and related psychotic disorders), bipolar disorder and psychotic depression, were eligible. Data from studies selected for inclusion were converted into ORs, with a subsequent meta-analysis conducted.FindingsWe included 19 studies with a total of 194 123 patients with SMI with different diagnoses and drawn from the general population. The pooled OR for physical multimorbidity in people with versus without SMI was 1.84 (95% CI 1.33 to 2.54), with the analysis indicating a high level of heterogeneity (98.38%). The other 15 studies included in the systematic review for which it was not possible to conduct a meta-analysis showed strong associations between SMI and physical multimorbidity.ConclusionsThe current evidence highlights the link between SMI and physical multimorbidity. A multidisciplinary approach is now urgent to develop the best models of services tailored to patients with SMI with physical multimorbidities to improve physical, mental and social outcomes.PROSPERO registration numberCRD42023395165.