Studies have shown reduced life expectancy following moderate-severe traumatic brain injury (TBI) with death from unintentional poisoning (UP) being 11 times higher following TBI than in the general population. The characteristics of those who die of unintentional poisoning are compared with the characteristics of those who die of other causes (OC) in a retrospective cohort who received inpatient rehabilitation following TBI and enrolled in the TBI Model Systems National Database between 1989 and 2017 (n = 15,835 cases with 2,238 deaths recorded). Seventy-eight cases (3.5%) of deaths were the result of UP, 76% were the result of OC, and 20.5% were from an unknown cause. Among the UP deaths, 90% involved drugs (of these, 67% involved narcotic drugs and 14% involved psychostimulants), and 8% involved alcohol. Age-adjusted risk for UP death was associated with: white/non-Hispanic race/ethnicity, living alone, non-institutionalization, pre- and post-injury illicit drug use and alcohol/drug problem use, any alcohol use at last follow-up, better Functional Independence MeasureTM (FIM) scores, history of arrest, moderate disability (vs. severe disability or good recovery), less supervision needed, and greater anxiety. Adults who receive inpatient rehabilitation for TBI who die from UP are distinguishable from those who die of OC. Factors such as pre-injury substance use in the context of functional independence may be regarded as targets for prevention and/or intervention to reduce substance use and substance-related mortality among survivors of moderate-severe TBI. The current findings may have implications for medical care, surveillance, prevention, and health promotion.