IntroductionPeople with serious mental illness (SMI), which includes people with diagnoses of schizophrenia spectrum and bipolar disorders, face significant health inequality. This includes a life expectancy reduced by 15–20 years mostly due to premature cardiovascular disease (CVD) compared with the general population. Excess weight gain and related comorbidities are preventable risk factors for CVD. To improve the understanding and management of CVD in people with SMI, we will examine the association between SMI and: (1) weight change; (2) cardio-metabolic risk factors for CVD; and (3) incidence of and mortality from CVD. We will also (4) examine the incidence of referral to weight management services for people with SMI compared with people without SMI.Methods and analysisIn this retrospective cohort study, we will link general practice records from the UK Clinical Practice Research Datalink Aurum database. We will establish a cohort of patients diagnosed with SMI between 1998 and 2020 who are matched with up to four controls on age, sex, general practice and calendar year. We will use multivariable mixed-effects linear regression models and Cox proportional hazard models with sequential adjustment for potential confounders identified by separate directed acyclic graphs.Ethics and disseminationThis study has been reviewed and approved by the Independent Scientific Advisory Committee for Medicines and Healthcare products Regulatory Agency database research. The results will be published in a peer-reviewed journal.