OBJECTIVES: Individuals with serious mental illness (SMI), including schizophrenia, bipolar disorder, and major depressive disorder, with a risk factor for cardiovascular disease (CVD) are a vulnerable population with diminished quality of life, complicated treatment plans, and mortality rates two to three times higher than the overall US population, mostly due to CVD. Our objective was to determine if significant direct healthcare costs exist between patients with SMI and a CVD risk factor compared to those who only have single diagnosis of SMI. METHODS: Using the 2010-2015 Medical Expenditure Panel Survey (MEPS) data, a two-part model (logit/GLM) was used to estimate total direct health care expenditures among patients with SMI and a CVD risk factor. Patients for primary analyses were identified as those 18 years of age or older who had either or both a diagnosis of any SMI or a risk factor for CVD. RESULTS: We identified 2,117 patients who had both a SMI diagnosis and a CVD risk factor. Unadjusted total health care expenditures were $14,590 (CI 95%13,274-15,906) for patients with both a SMI and CVD risk factor, compared to $9,863 (CI 95% $6,872-$12,854) for patients with SMI and no CVD risk factor. Patients with both SMI and a CVD risk factor were 32% (p<0.0001) more likely to incur higher annual direct health care expenses compared to those with either a single diagnosis of SMI. CONCLUSIONS: The economic burden of SMI and a co-morbid CVD risk factor accounts for a disproportionate share of expenditures compared to patients without these risk factors. Given the large prevalence of CVD risk factors among patients with SMI, screening for these conditions should be prioritized for timely diagnosis, appropriate disease management, and to mitigate downstream health care expenditures.