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Abstract Objective To estimate the relationship between comorbid serious mental illness (SMI) diagnosis and 30-day medical-surgical readmissions. Methods In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) we searched five databases (2012 to 2017) to identify relevant articles on the relationship between SMI diagnosis and readmissions. We used the National Institute of Health's Quality Appraisal Tool for Observational Cohort and Cross-Sectional Studies guidelines to appraise studies and assess risk of bias. Data were narratively synthesized and a pooled random effects unadjusted odds ratio was estimated using meta-analysis. Heterogeneity was investigated using subgroup analysis and meta-regression. Results Our search yielded 424 articles after removing duplicates. Nine met inclusion criteria. All studies were retrospective observational cohort studies. The meta-analysis showed that people with SMI have greater odds of readmission than people without SMI (pooled OR 1.38, CI 1.23–1.56, I2 = 98.6%). There was heterogeneity in patient cohorts, study methodology, and definition of SMI. No significant possibility of publication bias was detected (Classic fail-safe N = 3480). Conclusion There is a meaningful relationship between SMI diagnosis and medical-surgical readmissions. Given the prevalence of SMI in patients hospitalized for medical-surgical problems and the heterogeneity of evidence, further research on sources of variation in outcomes is critically needed. [ABSTRACT FROM AUTHOR]