Few studies have examined the consequences of alcohol and drug abuse on TBI though they commonly co-occur. Both TBI and substance abuse independently result in neuropathological changes in the brain such as ventricular enlargement and cortical atrophy, thus it is reasonable to hypothesize that the combination of the two would result in more significant cerebral damage. In this study, 3 groups of patients—traumatically brain injured (TBI) with substance abuse (N = 19), TBI without substance abuse (N = 19), and substance abuse with no TBI (N = 16)—were compared with normal controls (N = 20) on several quantitative MRI (QMRI) measures. Since TBI most frequently occurs in older adolescents and young men, we examined only male participants between 16 and 30 years of age. Comparing young substance abusers to controls resulted in no QMRI differences. When controlling for head injury severity, the effects of substance abuse in combination with TBI resulted in greater atrophic changes than seen in any other group. TBI and substance abuse patients' neuropsychological test performances also were examined, and no differences were found among patient groups on any measures. These findings have implications for the deleterious interaction of substance abuse combining with TBI to result in greater neuropathological changes that can be detected by QMRI techniques. (JINS, 1999, 5, 593–608.)