People with severe mental illness (SMI) appear to have an elevated risk of death from cardiovascular disease, but results regarding cancer mortality are conflicting. To estimate this excess mortality and the contribution of antipsychotic medication, smoking, and social deprivation. Retrospective cohort study. United Kingdom's General Practice Research Database. Patients Two cohorts were compared: people with SMI diagnoses and people without such diagnoses. Main Outcome Measure Mortality rates for coronary heart disease (CHD), stroke, and the 7 most common cancers in the United Kingdom. A total of 46 136 people with SMI and 300 426 without SMI were selected for the study. Hazard ratios (HRs) for CHD mortality in people with SMI compared with controls were 3.22 (95% confidence interval [CI], 1.99-5.21) for people 18 through 49 years old, 1.86 (95% CI, 1.63-2.12) for those 50 through 75 years old, and 1.05 (95% CI, 0.92-1.19) for those older than 75 years. For stroke deaths, the HRs were 2.53 (95% CI, 0.99-6.47) for those younger than 50 years, 1.89 (95% CI, 1.50-2.38) for those 50 through 75 years old, and 1.34 (95% CI, 1.17-1.54) for those older than 75 years. The only significant result for cancer deaths was an unadjusted HR for respiratory tumors of 1.32 (95% CI, 1.04-1.68) for those 50 to 75 years old, which lost statistical significance after controlling for smoking and social deprivation. Increased HRs for CHD mortality occurred irrespective of sex, SMI diagnosis, or prescription of antipsychotic medication during follow-up. However, a higher prescribed dose of antipsychotics predicted greater risk of mortality from CHD and stroke. This large community sample demonstrates that people with SMI have an increased risk of death from CHD and stroke that is not wholly explained by antipsychotic medication, smoking, or social deprivation scores. Rates of nonrespiratory cancer mortality were not raised. Further research is required concerning prevention of this mortality, including cardiovascular risk assessment, monitoring of antipsychotic medication, and attention to diet and exercise.