Background Psychiatric patients are known to have poorer physical health than the general population and to have premature mortality, but the impact of institutional care on the physical health of patients is less clear. Aims This study aimed to compare mortality rates and causes of death between a high‐security psychiatric hospital cohort and the general population in England for the periods 1920–1961 and 1972–2000. Method Data were obtained from various clinical and non‐clinical archives and death certificates. Standardised mortality ratios were calculated for all causes of patient death for each International Classification of Diseases, 10th Edition category. Results Mortality rates of men ever resident in Rampton Hospital were similar to those of men in the general population, but women in Rampton Hospital had nearly twice the national death rate. Younger men in the latest time period (1972–2000), however, had a higher mortality rate. Higher mortality rates in the hospital than in the general population were accounted for by infectious and parasitic diseases as well as diseases of the nervous system; rates of neoplasms and diseases of the blood and of circulatory or respiratory diseases were lower among the patients. Clinical implications Specific‐cause mortality rates were compatible with our working hypothesis that the hospital could in some ways pose risks and in other ways be protective. Morbidity and causes of premature death may be environment‐specific, so recognition of the types of illness linked to premature death among high‐security hospital patients could inform improvements in the physical health of long‐stay patients. Further longitudinal studies should be undertaken to monitor trends and inform changes needed to reduce premature mortality. Copyright © 2015 John Wiley & Sons, Ltd.