A cohort design was used to determine the contribution of traumatic brain injury (TBI) and psychiatric illness to health care costs for adolescents and adults in the 3 years following mild or moderate-to-severe TBI compared to a matched cohort without TBI, controlling for confounders. In all, 3756 subjects 15 years or older from a large health maintenance organization database were examined. We identified subjects who sustained a TBI in 1993 (n=939) and selected three control subjects per TBI-exposed subject (n=2817), matched for age, sex, and enrollment at the time of injury. Unadjusted mean costs in 2009-adjusted dollars were compared using Kruskal-Wallis tests and Mann-Whitney U tests, and adjusted mean costs were compared using gamma regression analyses. Average costs were 76% higher in the 3 years after injury for the mild TBI group, and 5.75 times greater for the moderate-to-severe TBI group compared to controls. The presence of psychiatric illness was associated with more than doubling of total costs for both inpatient and outpatient non-mental health care. Gamma regression analyses confirmed significantly higher costs in patients with TBI or psychiatric illness. A significant interaction between moderate-to-severe TBI and psychiatric illness indicated a 3.39 times greater cost among patients with both exposures compared with those exposed to moderate-to-severe TBI without psychiatric illness. TBI and psychiatric illness were each associated with significant increases in health care costs; those with the combination of moderate-to-severe TBI and psychiatric illness had much higher costs than any other group.