Background: Although people with serious mental illnesses have a high risk of contracting blood-borne viral infections, sexual health has largely been neglected by researchers and policy makers involved in mental health. Failure to address this shortcoming could increase morbidity and mortality as a result of undetected and untreated infection. We did a systematic review and meta-analysis to estimate the prevalence of blood-borne viral infection in people with serious mental illness. Method: We searched the Cochrane Library, Medline, Embase, PsycInfo, CINAHL, and DARE for studies of the prevalence of HIV, hepatitis B virus, and hepatitis C virus in people with serious mental illness, published between Jan 1, 1980, and Jan 1, 2015. We group prevalence data by region and by virus and estimated pooled prevalence. We did a sensitivity analysis of the effect of study quality on prevalence. Findings: After removal of duplicates, we found 373 abstracts, 91 of which met our eligibility criteria. The prevalences of blood-borne viral infections in people with serious mental illness were higher than in the general population in places with low prevalence of blood-borne viruses, such as the USA and Europe, and on par with the general population in regions with high prevalence of blood-borne viruses (Africa for HIV and southeast Asia for hepatitis B virus and hepatitis C virus). Pooled prevalence of HIV in people with serious mental illness in the USA was 6·0% (95% CI 4·3-8·3). Sensitivity analysis showed that quality scores did not significantly affect prevalence. Interpretation: People with serious mental illness are at risk of blood-borne viral infections. However, because of methodological limitations of the studies the prevalence might be overestimated. Serious mental illness is unlikely to be a sole risk factor and risk of blood-borne viral infection is probably multifactorial and associated with low socioeconomic status, drug and alcohol misuse, ethnic origin, and sex. Health providers should routinely discuss sexual health and risks for blood-borne viruses (including risks related to drug misuse) with people who have serious mental illness, as well as offering testing and treatment for those at risk. Funding: Wellcome Trust.