An increasing number of patients are able to survive traumatic brain injuries (TBIs) with advanced resuscitation. However, the role of their pre-injury health status in mortality in the following years is not known. Here, we followed 77,088 consecutive patients (59% male) who survived the TBI event in Ontario, Canada for more than a decade, and examined the relationships between their pre-injury health status and mortality rates in excess to the expected mortality calculated using sex- and age-specific life tables. There were 5792 deaths over the studied period, 3163 (6.95%) deaths in male and 2629 (8.33%) in female patients. The average excess mortality rate over the follow-up period of 14 years was 1.81 (95% confidence interval = 1.76-1.86). Analyses of follow-up time windows showed different patterns for the average excess rate of mortality following TBI, with the greatest rates observed in year one after injury. Among identified pre-injury comorbidity factors, 33 were associated with excess mortality rates. These rates were comparable between sexes. Additional analyses in the validation dataset confirmed that these findings were unlikely a result of TBI misclassification or unmeasured confounding. Thus, detection and subsequent management of pre-injury health status should be an integral component of any strategy to reduce excess mortality in TBI patients. The complexity of pre-injury comorbidity calls for integration of multidisciplinary health services to meet TBI patients’ needs and prevent adverse outcomes.Copyright © 2020. Published by Elsevier Inc.