ImportanceTranscutaneous osseointegration post amputation (TOPA) creates a direct linkage between residual bone and an external prosthetic limb, providing superior mobility and quality of life compared with a socket prosthesis. The causes and potential risks of mortality after TOPA have not been investigated.ObjectiveTo investigate the association between TOPA and mortality and assess the potential risk factors.Design, Setting, and ParticipantsThis observational cohort study included all patients with amputation of a lower extremity who underwent TOPA between November 1, 2010, and October 31, 2021, at a specialty orthopedic practice and tertiary referral hospital in a major urban center. Patients lived on several continents and were followed up as long as 10 years.ExposuresTranscutaneous osseointegration post amputation, consisting of a permanent intramedullary implant passed transcutaneously through a stoma and connected to an external prosthetic limb.Main Outcomes and MeasuresDeath due to any cause. The hypotheses tested—that patient variables (sex, age, level of amputation, postosseointegration infection, and amputation etiology) may be associated with subsequent mortality—were formulated after initial data collection identifying which patients had died.ResultsA total of 485 patients were included in the analysis (345 men [71.1%] and 140 women [28.9%]), with a mean (SD) age at osseointegration of 49.1 (14.6) years among living patients or 61.2 (12.4) years among patients who had died. Nineteen patients (3.9%) died a mean (SD) of 2.2 (1.7) years (range, 58 days to 5 years) after osseointegration, including 17 (3.5%) who died of causes unrelated to osseointegration (most commonly cardiac issues) and 2 (0.4%) who died of direct osseointegration-related complications (infectious complications), of which 1 (0.2%) was coclassified as a preexisting health problem exacerbated by osseointegration (myocardial infarction after subsequent surgery to manage infection). No deaths occurred intraoperatively or during inpatient recuperation or acute recovery after index osseointegration (eg, cardiopulmonary events). Kaplan-Meier survival analysis with log-rank comparison and Cox proportional hazards regression modeling identified increased age (hazard ratio, 1.06 [95% CI, 1.02-1.09]) and vascular (odds ratio [OR], 4.73 [95% CI, 1.35-16.56]) or infectious (OR, 3.87 [95% CI, 1.31-11.40]) amputation etiology as risk factors. Notable factors not associated with mortality risk included postosseointegration infection and male sex.Conclusions and RelevanceThese findings suggest that patients who have undergone TOPA rarely die of problems associated with the procedure but instead usually die of unrelated causes.