Abstract Background Patients with severe mental illness (SMI), such as schizophrenia or bipolar disorders, are more frequently affected by metabolic syndrome and cardiovascular (CVD) diseases than the general population, with a significant reduction in life expectancy. Purpose Beyond metabolic syndrome, quantifying the risk of CVD morbidity in the long-term may help clinicians to put in place preventive strategies. In this study, we assessed 10-year CVD risk in patients with SMI and healthy individuals using an algorithm validated previously. Methods Patients aged 35–69 years diagnosed with SMI were consecutively recruited from psychiatric acute care units. Single CV risk factors were assessed, and 10-year CV risk calculated by means of the CUORE Project 10-year CV risk algorithm, based on the combination of the following risk factors: age, systolic blood pressure, total and high-density lipoprotein cholesterol, diabetes, smoking habit, and hypertensive treatment. Patients’ data were compared with those from the general population. The 10-year CVD risk was log-transformed, and multivariable linear regression was used to estimate mean ratios, adjusting for age, and education. Results Three hundred patients and 302 controls were included in the analysis. Among men, the 10-year CVD risk score was very similar between patients with SMI and the general population (mean ratio (MR): 1.02; 95%CI 0.77–1.37), whereas a 39% increase in 10-year CVD risk was observed in women with SMI compared to the general population (MR: 1.39; 95%CI 1.16–1.66). Conclusions In our study, women with SMI were consistently more at risk than the general population counterpart, even at younger age.