BACKGROUND: Patients undergoing primary total joint replacement are selected for surgery and thus (other than having a transiently increased mortality rate postoperatively) have a lower mortality rate than age and sex-matched individuals do. Understanding the causes of death following joint replacement would allow targeted strategies to reduce the risk of death and optimize outcome. We aimed to determine the rates and causes of mortality for patients undergoing primary total hip or knee replacement compared with individuals in the general population who were matched for age and sex. METHODS: We compared causes and rates of mortality between age and sex-matched individuals in the general population (National Joint Registry for England, Wales and Northern Ireland; Hospital Episode Statistics; and Office for National Statistics) and a linked cohort of 332,734 patients managed with total hip replacement (26,766 of whom died before the censoring date) and 384,291 patients managed with primary total knee replacement (29,802 of whom died before the censoring date) from 2003 through 2012. RESULTS: The main causes of death were malignant neoplasms (33.8% [9,037] of 26,766 deaths in patients with total hip replacement and 33.3% [9,917] of 29,802 deaths in patients with total knee replacement), circulatory system disorders (32.8% [8,784] of the deaths in patients with total hip replacement and 33.3% [9,932] of the deaths in patients with total knee replacement), respiratory system disorders (10.9% [2,928] of the deaths in patients with total hip replacement and 9.8% [2,932] of the deaths in patients with total knee replacement), and digestive system diseases (5.5% [1,465] of the deaths in patients with total hip replacement and 5.3% [1,572] of the deaths in patients with total knee replacement). There was a relative reduction in mortality (39%) compared with the individuals in the general population that equalized to the rate in the general population by 7 years for hips (overall standardized mortality ratio [SMR], 0.61; 95% confidence interval [CI], 0.60 to 0.62); for knees, the relative reduction (43%) partially attenuated by 7 years but still had not equalized to the rate in the general population (overall SMR, 0.57; 95% CI, 0.56 to 0.57). Ischemic heart disease was the most common cause of death within 90 days (29% [431] of the deaths in patients with primary hip replacement and 31% [436] of the deaths in patients with primary knee replacement). There was an elevated risk of death from circulatory, respiratory, and (most markedly) digestive system-related causes within 90 days postoperatively compared with 91 days to 1 year postoperatively. CONCLUSIONS: Ischemic heart disease is the leading cause of death in the 90 days following total joint replacement, and there is an increase in postoperative deaths associated with digestive system-related disease following joint replacement. Interventions targeted at reducing these diseases may have the largest effect on mortality in total joint replacement patients. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.