Combat exposure is associated with increased risk of psychiatric and substance use disorders in veterans. However, it is not known whether combat exposure independently increases risk for these disorders or whether this association is accounted for by genetic vulnerability common to posttraumatic stress disorder (PTSD). This article tests competing explanations for the association of combat exposure and PTSD with nicotine dependence (ND), alcohol dependence (AD), and major depression (MD). Data were obtained from 6099 members of the Vietnam Era Twin Registry, a national registry of male-male twin pairs who served in the military during the Vietnam era. Twin models were fit to estimate the genetic and environmental variance common and specific to Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, lifetime diagnoses of PTSD, combat trauma, and 3 comorbid conditions: ND, AD, and MD. Variance specific to ND, AD, and MD was due to genetic factors (48%, 36%, and 12%, respectively) and unique environmental factors (36%, 42%, and 58%, respectively). After accounting for variance common to PTSD, no residual genetic and environmental variance overlapped between combat and ND, combat and AD, and combat and MD. Combat exposure is not independently associated with lifetime ND, AD, and MD. The association of combat exposure with these 3 disorders is due to genetic and unique environmental contributions in common with PTSD. These findings suggest comorbid PTSD may represent a genetically mediated vulnerability to psychopathology after trauma.