Physical and psychological trauma frequently co-occur, resulting in individuals presenting for treatment with multiple targets for intervention. Specifically, traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) are often comorbid. Trauma-focused therapies such as cognitive processing therapy (CPT) are feasible and effective in this population, although the co-occurrence of TBIs and PTSD nonetheless presents some unique treatment challenges. This chapter will summarize the empirical background and support for the feasibility and effectiveness of CPT in reducing PTSD and neurobehavioral symptoms in those with PTSD and a history of TBI. Barriers to engagement in psychotherapy for individuals with both PTSD and persistent symptoms following TBI will be addressed as well as suggestions to combat these roadblocks. Insomnia and chronic pain are additional physical health conditions that also commonly present with PTSD and history of TBI, adding additional treatment complexity. The intertwined nature of TBI and PTSD and these other physical health comorbidities respond best to holistic intervention approaches that target multiple symptoms in concert. A detailed example of one such treatment is provided.